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Comparison Between Non-Invasive Coronary Flow Reserve and Fractional Flow Reserve to Assess the Functional Significance of Left Anterior Descending Artery Stenosis of Intermediate Severity
Comparison Between Non-Invasive Coronary Flow Reserve and Fractional Flow Reserve to Assess the Functional Significance of Left Anterior Descending Artery Stenosis of Intermediate Severity Patrick Meimoun, MD, Smain Sayah, MD, Anne Luycx-Bore, MD, Jacques Boulanger, MD, Frederic Elmkies, MD, Tahar Benali, MD, Hamdane Zemir, MD, Luc Doutrelan, MD, and Jerome Clerc, MD, Compie gne, France
Background: Assessment of the functional significance of left anterior descending coronary artery (LAD) stenosis of intermediate severity (50%–70% diameter stenosis) is challenging. The aim of this study was to compare the value of noninvasive coronary flow reserve (CFR) with that of invasive fractional flow reserve (FFR) in the setting of LAD stenosis of angiographic intermediate severity. Methods: Fifty stable consecutive patients (mean age, 63 6 13 years; 11 women; mean left ventricular ejection fraction, 61 6 10%) with angiographic proximal LAD stenoses of intermediate severity (55.5 6 5% diameter stenosis on quantitative coronary angiography), no previous anterior myocardial infarction, and various vascular risk factors were prospectively studied. They underwent FFR assessment with intracoronary bolus adenosine (150 mg), and CFR assessment using intravenous adenosine (140 mg/kg/min over 2 min) in the distal part of the LAD on the same day in nearly all patients. CFR was defined as hyperemic peak diastolic LAD flow velocity divided by baseline flow velocity (normal value >2), and FFR was defined as distal pressure divided by mean aortic pressure during maximal hyperemia (normal value >0.8). Results: The mean FFR and CFR were 0.84 6 0.07 and 2.7 6 0.75, respectively, in the whole population. Concordant results between FFR and CFR were seen in 44 patients (88%) and discordant results in six patients (12%). There was a significant correlation between CFR and FFR (r = 0.59, P < .01). A better correlation was found between FFR and percentage LAD diameter stenosis, and lesion length (all P values < .05), than between CFR and the same anatomic markers of stenosis severity (all P values = NS). The sensitivity, specificity, and positive and negative predictive values of CFR >2 to detect a nonsignificant lesion defined by normal FFR were 95%, 69%, 90%, and 82%, respectively. Conclusions: In patients with LAD stenosis of intermediate severity, discordant results between noninvasive CFR and FFR were not unusual, and the anatomic determinants of the stenosis were better correlated to FFR than to CFR. However, CFR, which is a global evaluation of the coronary tree, has very high sensitivity to detect a nonsignificant lesion, despite the high prevalence of vascular risk factors. (J Am Soc Echocardiogr 2011;24:374-81.) Keywords: Coronary flow reserve, Fractional flow reserve, Intermediate coronary stenosis, Doppler echocardiography
The physiologic significance of coronary stenosis of intermediate severity on angiography is important for clinical decision making but is difficult to assess.1-4 Coronary angiography alone cannot accurately predict the significance of most intermediate stenoses. In this setting, there is a poor correlation with stress testing to predict the functional significance of stenosis and high interobserver variability in evaluating gne Hospital, From the Department of Cardiology and Intensive Care Unit, Compie gne, France. Compie Reprint requests: Patrick Meimoun, MD, Department of Cardiology and Intensive Care Unit, Centre Hospitalier de Compiegne, 8 rue Henri Adnot, 60200 gne, France (E-mail: [email protected]). Compie 0894-7317/$36.00 Copyright 2011 by the American Society of Echocardiography. doi:10.1016/j.echo.2010.12.007
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coronary stenosis severity on the basis of angiography alone.1-6 Therefore, according to the discordance between anatomy and function, proof that a stenosis is functionally significant is needed before attempting revascularization in this setting.1-7 Fractional flow reserve (FFR), available in the catheterization laboratory, is well recognized as the gold standard to evaluate these stenoses.4,5 On the basis of the measurement of the translesional pressure gradient during hyperemia, this tool assesses accurately the physiologic significance of a stenosis, and recent studies have demonstrated its important prognostic value.4,8 However, FFR is not available in all catheterization laboratories, and given its invasive nature, it is not suitable for the potential follow-up of stenoses treated medically, which may progress and become significant. Coronary flow reserve (CFR) measured by transthoracic Doppler echocardiography is a very attractive tool for the assessment of coronary
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stenoses of intermediate severity. It allows the noninvasive evaluaCFR = Coronary flow reserve tion of a stenosis at bedside and also provides prognostic value in FFR = Fractional flow reserve this setting.6,7,9-11 However, CFR LAD = Left anterior is a global evaluation of the descending coronary artery coronary tree theoretically limited by concomitant illnesses affecting the coronary microcirculation, which is not the case for FFR. Furthermore, in daily clinical practice, patients with intermediate coronary stenoses have various vascular risk factors that could influence the coronary microcirculation and affect CFR. A direct comparison of FFR and noninvasive CFR has never been performed, particularly in the setting of coronary stenoses of intermediate severity. Therefore. our objective was to assess the reliability of noninvasive CFR in comparison with FFR in the same group of stable patients with left anterior descending coronary artery (LAD) stenoses of angiographic intermediate severity. Abbreviations
METHODS Fifty consecutive patients admitted to our institution for diagnostic coronary angiography who had LAD stenoses of angiographic intermediate severity (50%–70%) prospectively underwent FFR and CFR to assess the functional significance of the stenoses for which the angiographer was unable to make a decision regarding revascularization based solely on the angiogram because stress testing was not performed, was inconclusive, or was ambiguous in most cases. CFR and FFR were performed the same day in the majority of patients (n = 42), in random order, and between 2 days and 1 week apart in the remainder of patients (n = 8) for logistic reasons. The reasons for coronary angiography were as follows: acute coronary syndromes involving arteries other than the LAD (n = 14), chest pain with positive or inconclusive exercise electrocardiographic or stress testing results (n = 19) or without documented ischemia (n = 6), suggestion of restenosis after angioplasty (n = 3), heart failure assessment (n = 5), and other (n = 3). Among the patients who underwent myocardial perfusion imaging or stress echocardiography (n =10), nine were considered to have ischemia, five in territories not matching the LAD territory and four in the LAD territory. Exclusion criteria were previous anterior myocardial infarction and acute coronary syndromes involving the LAD, stenosis in the distal part of the LAD, severe valvular disease, and contraindication to adenosine (asthma, high-degree atrioventricular block). Patients with acute coronary syndromes involving arteries other than the LAD could be included in the study if successful percutaneous coronary angioplasty was performed in all patients $2 weeks previously. All patients were in stable sinus rhythm and continued their cardiac medications at the time of FFR and CFR. They all presented with stable coronary artery disease at the time of the tests. Inform consent was obtained from all patients. Coronary Angiography Selective coronary angiography was performed using standard techniques via the femoral or radial approach. The severity of coronary stenosis was evaluated by multiple projections and was determined by experienced investigators with commercially available quantitative coronary angiographic software program (Integris HM 3000; Philips Medical Systems, Andover, MA). Using the guiding catheter as a scaling device, reference diameter, minimal luminal diameter, and percentage diameter stenosis were calculated.
FFR Coronary pressure was measured with a commercially 0.014-inch pressure monitoring guidewire (PrimeWire; Volcano Corporation, San Diego, CA). The wire was introduced through a 6Fr or 7Fr guiding catheter, calibrated, advanced into the coronary artery, and positioned about 3 cm distal to the stenosis. Mean aortic and distal pressure were measured at baseline and during an intracoronary bolus of 150 mg adenosine.12 FFR was defined as previously described4,5 as the ratio of mean hyperemic distal coronary pressure measured using the pressure wire to mean aortic pressure measured using the guiding catheter during maximal hyperemia. An abnormal value of FFR was defined as <0.8.4 Heart rate, distal pressure, and aortic pressure were continuously recorded and digitally stored during the procedure. Final values of FFR represented an average value of three cardiac cycles. CFR Noninvasive CFR was performed with commercially available machines (Acuson Sequoia 256, Siemens Medical Solutions, USA, Inc., Mountain View, CA; and Vivid E9, GE Healthcare, Milwaukee, WI) as previously described.13,14 Briefly, CFR was assessed in the distal part of the LAD using a low multifrequency transducer (3V2C or M5S probe), downstream to the LAD stenosis in all cases. Visualization of the artery was performed with color Doppler flow mapping guidance. For color Doppler echocardiography, the velocity range was set in the range of 12 to 19 cm/sec. Blood flow velocity was measured by pulsed-wave Doppler echocardiography using a sample volume of 3 to 4 mm placed on the color signal in the distal LAD. Noninvasive CFR was measured during intravenous infusion of adenosine (0.14 mg/kg/min over 2 min). Blood flow velocity measurements were performed offline by an experienced investigator who was blinded to the patient data by contouring the spectral Doppler signals using the integrated software package of the ultrasound system. CFR was calculated as the ratio of hyperemic to basal peak diastolic flow velocities. Final values of flow velocity represented an average of three cardiac cycles. The electrocardiogram was monitored continuously throughout adenosine infusion. Blood pressure and heart rate were measured at baseline and at the time of peak action of adenosine. An abnormal value of CFR was defined as <2.6,7,9-11,15-18 To improve visualization of the color Doppler signal and/or to obtain clear spectral Doppler signals in the LAD, a contrast agent was used in seven patients (14%) (SonoVue; Bracco, Milan, Italy) and administrated intravenously as a 0.1-mL bolus. The interobserver and intraobserver variability for CFR measurements in our experience have been previously reported (about 4%).6,14 Statistical Analysis Results are expressed as mean 6 SD and percentages. Categorical variables were compared using c2 analysis or Fisher’s exact test as appropriate, and continuous variables were compared using Student’s t test for paired or unpaired data. The relationships between FFR, CFR, percentage LAD diameter stenosis, percentage LAD area stenosis, and lesion length were evaluated using linear and nonlinear correlations, and those exhibiting the best fit were retained. Statistical analysis was performed using MedCalc for Windows version 10.6.0.0 (MedCalc Software, Mariakerke, Belgium). P values < .05 were considered significant.
RESULTS Baseline characteristics of the study population are listed in Table 1. The mean age was 63 6 13 years, with 11 women (22%).
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Table 1 Baseline characteristics (n = 50) Variable
Table 3 Doppler echocardiographic characteristics (n = 50) Value
Age (y) Women/men BMI (kg/m2) Diabetes Hypertension Smoking Dyslipidemia b-blockers Aspirin Statins ACE inhibitors/ARBs Clopidogrel Previous MI Previous PCI
63 6 13 11/39 27.5 6 4.5 9 (18%) 27 (54%) 15 (30%) 35 (70%) 42 (84%) 49 (98%) 45 (90%) 39 (78%) 41 (82%) 12 (24%) 28 (56%)
Data are expressed as mean 6 SD or as number (percentage). ACE, Angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BMI, body mass index; MI, myocardial infarction; PCI, percutaneous coronary intervention.
Table 2 Angiographic data (n = 50) Variable
Value
Minimal luminal diameter (mm) Reference luminal diameter (mm) Percentage LAD stenosis (%) Lesion length (mm) Percentage area stenosis (%) Proximal LAD/mid-LAD FFR FFR <0.8 Type of stenosis A B1 B2 C Baseline systolic blood pressure (mm Hg) Baseline diastolic blood pressure (mm Hg) Baseline heart rate (beats/min) Baseline RPP (mm Hg $ beats/min $ 103)
1.34 6 0.32 3.01 6 0.59 55.5 6 5 14.1 6 6.5 79.9 6 4.7 26 (52%)/24 (48%) 0.84 6 0.08 13 (26%) 2 (4%) 16 (32%) 24 (48%) 8 (16%) 128 6 22 76 6 8 67 6 11 8.6 6 2.4
Data are expressed as mean 6 SD or as number (percentage). RPP, Rate-pressure product.
Histories of posterior-inferior myocardial infarction were seen in 12 patients (24%), and 28 patients (56%) underwent previous angioplasty. Both tests were well tolerated, with no serious adverse events. Angiographic and Doppler echocardiographic parameters are summarized in Tables 2 and 3, respectively. No significant differences were seen among hemodynamic data between the two exams (all P values = NS). The mean percentage LAD stenosis was 55.5 6 5%. All patients had successful CFR evaluations, with the help of a contrast agent in 14%. The mean CFR was 2.7 6 0.75 (range, 1.3–4.4), and the mean FFR was 0.84 6 0.07 (range, 0.65–0.98). An illustrative case is depicted in Figure 1.
Variable
Value
Baseline LAD flow velocity (cm/sec) Hyperemic LAD flow velocity (cm/sec) CFR CFR <2, n (%) Baseline heart rate (beats/min) Baseline systolic blood pressure (mm Hg) Baseline diastolic blood pressure (mm Hg) Baseline RPP (mm Hg $ beats/min $ 103) LV ejection fraction (%) LV mass index (g/m2) E/Ea ratio PASP (mm Hg)
27 6 7 70.5 6 19 2.7 6 0.75 11 (22%) 65 6 12 133 6 21 70 6 11 8.6 6 2.2 61 6 10 91 6 19 8.5 6 5 30 6 7
Data are expressed as mean 6 SD or as number (percentage). LV, Left ventricular; PASP, pulmonary artery systolic pressure; RPP, rate-pressure product.
Correlations There was a weak but significant correlation between CFR and FFR (r = 0.59, P < .01; Figure 2). Better correlations were found between FFR and percentage LAD diameter stenosis, percentage LAD area stenosis, and lesion length (all P values < .05) than between CFR and the same anatomic markers of stenosis severity (all P values = NS) (see Figure 3). FFR and CFR Above and Below the Threshold Values Patients with low CFR (n = 11) were more frequently diabetics (45% vs 10%, P = .02), had lower left ventricular ejection fractions (P < .05), had lower FFR (0.74 6 0.06 vs 0.86 6 0.05, P < .001), and had higher percentage LAD diameter stenoses (58.6 6 7% vs 54.6 6 5%, P = .03) than patients with CFR >2, whereas other demographic, hemodynamic, Doppler echocardiographic, and angiographic variables did not differ significantly between these subgroups (all P values = NS). Compared with patients with FFR >0.8, those with low FFR were more frequently diabetics (45% vs 10%, P = .02), had higher percentage LAD diameter stenoses (60.6 6 7% vs 54 6 4%, P = .01) and percentage LAD area stenoses (P = .05), had lower CFR (2.2 6 0.7 vs 2.9 6 0.7, P < .01), and showed a trend toward longer lesion length (P = .08). Discordant and Concordant Results Among the 37 patients who had FFR >0.8, 35 had CFR >2, and among the 13 patients with FFR #0.8, nine had CFR #2 (see Figure 2). Therefore, the sensitivity, specificity, and positive and negative predictive values for CFR to detect a nonsignificant lesion (defined as FFR >0.8) were 95.5%, 69%, 90%, and 82%, respectively, with an accuracy of 88%.
DISCUSSION Noninvasive CFR has already been compared with various tools, such as angiography,18 invasive Doppler flow wire,19,20 nuclear cardiac imaging,7 and stress echocardiography,6,10 but curiously, no specific data are available on noninvasive CFR and FFR. A few studies have compared invasive CFR with FFR in patients with intermediate
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Figure 1 Illustrative case. A 70-year old man with chest pain and inconclusive stress test results. (Bottom right) Coronary angiography showed a long 50% mid-LAD stenosis. (Top) FFR was 0.86. (Bottom left) Noninvasive CFR was concordant with a mean value at 2.9 (basal and hyperemic flow velocities are depicted, demonstrating a biphasic pattern with diastolic predominance). stenoses,15,16 but to our knowledge, ours is the first to compare noninvasive CFR with FFR, the method of choice for the functional evaluation of a coronary stenosis. FFR is a measure of a pressure gradient across a coronary stenosis during hyperemia, regardless of the flow that passes through the stenosis, or of microvascular resistance, whereas CFR is the ratio of hyperemic coronary flow relative to baseline, regardless of the concomitant pressure gradient across the stenosis. However, there is a curvilinear relationship between the pressure drop across a stenosis and coronary flow, and dealing with only one of the components could lead to missing data about the stenosis properties. Despite these limitations, FFR has several advantages over other techniques for the evaluation of stenosis severity, including its specificity to epicardial lesions, independence from hemodynamic alterations, and high spatial resolution and reproducibility.4,5,17 By contrast, CFR is influenced by hemodynamics and the coronary microcirculation.17,21 Hyperemic flow, which is linearly related to coronary perfusion pressure, depends on total coronary resistance (epicardial vessel, small arteries, arterioles, and intramyocardial capillary system), whereas baseline flow is influenced by several factors, including myocardial oxygen demand and vasomotor tone. Other factors influence CFR, such as aging, left ventricular mass, drugs, habits, sexual hormones, and left ventricular end-diastolic wall stress.17,21,22 Therefore, when one would assess the functional significance of an epicardial coronary stenosis using CFR, one should be aware of all these influencing factors when interpreting the results. Given these considerations, it is not surprising to find that the anatomic determinants of stenosis severity, such as percentage LAD
Figure 2 Scatterplot of the curvilinear relationship between noninvasive CFR and FFR. Horizontal and vertical dashed lines are depicted at the set points of CFR of 2 and FFR of 0.8, respectively, to show the limit between normal and abnormal values.
diameter stenosis, lesion length, and percentage LAD area stenosis, were significantly correlated with FFR but not CFR in these intermediate stenoses. Despite these drawbacks, the use of CFR in this study demonstrated good accuracy to detect a nonsignificant lesion in comparison with FFR. Indeed, in 88% of cases,
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Figure 3 Relationship between the anatomic determinants of the stenosis and CFR and FFR. (A) Percentage LAD diameter stenosis. (B) Percentage area stenosis. (C) Lesion length. noninvasive CFR assessment of the LAD matched with invasive FFR, which matched well with invasive angiography. Diabetes was associated with both impaired CFR and FFR in this study, high-
lighting the negative impact of this disease on the whole coronary tree, as shown recently in patients with acute myocardial infarction.23
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Prognostic Value of CFR and FFR Several studies have demonstrated the prognostic value of FFR in patients with intermediate coronary stenosis.24 A revascularization of a lesion with FFR >0.75 to 0.8 can safely be deferred for up to 5 years.8 However, on an individual basis, close follow-up is mandatory for patients with functionally nonsignificant stenoses treated medically. A noninvasive test such as CFR could be useful in this setting to detect a progression of disease. Few studies also showed the prognostic value of invasive25-27 and noninvasive CFR9-11 in patients with intermediate stenosis, but a direct comparison between noninvasive CFR and FFR is lacking. Comparison of CFR and FFR Discordant results between CFR and FFR were found in six patients (12%), which is rather low compared with the 27% found in an invasive study.15 The different methodologies and populations studied may partially account for these differences. In this study, an invasive Doppler flow wire was used to assess CFR in a group of 126 patients with stable angina, with 150 intermediate coronary stenoses between 40% and 70% by visual assessment, and the cutoff value of normal FFR was lower (0.75), as was the intracoronary dose of adenosine used. Seventeen percent of lesions had normal CFR and low FFR, and 10% had low CFR and normal FFR. This latter group was characterized by a higher hyperemic vascular resistance and baseline flow, whereas the former group had a higher diameter stenosis. Indeed, when taking into account both the pressure gradient and the flow across the stenosis during hyperemia, the accuracy to detect reversible defect with nuclear cardiac imaging is higher than when using CFR or FFR alone (87% vs 75%).16 In addition, noninvasive CFR differs slightly from invasive CFR using a Doppler flow wire: the angle between the Doppler beam and the artery is more pronounced, and the systolic component of the flow is not usually used for CFR calculation with the noninvasive method, and the site of flow velocity measurement is not necessarily the same. Despite these differences, the correlation between CFR and FFR are quite similar, 0.59 in our study and 0.6 in the invasive study cited above.15 Because CFR interrogates the entire coronary system, including both the conduit and the resistive vessels, and because FFR is an evaluation of the epicardial coronary tree, the patients with low CFR (<2) and ‘‘normal’’ FFR (>0.8) could be interpreted as patients with mainly coronary microvascular impairment. However, despite the prevalence of a substantial proportion of various vascular risk factors, which could also affect the microcirculation, in our population, the sensitivity for CFR to detect a nonsignificant lesion, defined as FFR >0.8, was very high (95%). Noninvasive CFR using a cutoff value of 2 also detects with good precision significant LAD stenosis by angiography in a wide range of stenosis severity, despite a high potential for coronary microvascular impairment.18 The high dose of intracoronary adenosine used in our study reduces the likelihood of insufficient hyperemia for FFR evaluation12 as another explanation for this discrepancy. Patients with low FFR and ‘‘normal’’ CFR were not frequently seen in our study (n = 4 [8%]), and several hypothesis might explain these discrepancies. On the basis of previous results and according to the ischemic threshold, a normal value of CFR was defined as >2.6,911,15-18 Unlike FFR, which has a universal normal value of 1, one can speculate that CFR does not have the same normal value in every patient, and it could be much higher in some patients with low FFR and CFR >2. Interestingly, noninvasive CFR improved significantly within 24 hours after angioplasty in two patients with low FFR and ‘‘normal’’ CFR (from 2.6 to 3.4 and 3.6, respectively).
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Another reason for explaining this divergence is provided by the variability of microvascular resistance, which influences FFR and CFR in opposite directions, particularly in the setting of intermediate stenoses.15,16 Indeed, distal pressure depends on flow across the stenosis, which is determined by both epicardial and microvascular resistance.15 For a given epicardial stenosis resistance, a change in microvascular resistance affects distal pressure and flow in opposite directions. In other words, when there is a low microvascular resistance at hyperemia, the flow across the stenosis increases, distal pressure decreases, and therefore FFR will be lower. In contrast, CFR is preserved. Finally, one limitation of the noninvasive evaluation of CFR on LAD is the possibility of the interrogation of a well-developed, nonstenotic diagonal branch that runs in parallel with the LAD. The consequence will be normal CFR in the interrogated vessel and low FFR in the LAD. However, this situation is rare in our experience, and septal branches when visible could unambiguously detect the LAD by color Doppler flow interrogation. Furthermore, if the sampling site of the coronary flow is proximal to the stenosis, CFR may be normal, as there are side branches between the sampling site and the stenosis, which reflects perfusion in normal territories. To avoid this situation, distal stenoses were exclusion criteria, and careful attention was made to measure the flow at the distal part of the LAD, downstream to the stenosis. Because CFR is a noninvasive evaluation, technical limitations could also explain the discordant results between CFR and FFR, such as a poor signal, poor technical acquisition (limited by the use of a contrast agent), or some measuring variability. Limitations Coronary thermodilution-derived CFR has been developed in recent years and permits the simultaneous assessment of CFR and FFR using a single coronary pressure wire.28 However, this technique is not available in our catheterization lab, and our goal was to compare noninvasive CFR and FFR to validate the noninvasive evaluation of intermediate stenoses against FFR. We compared noninvasive CFR with FFR in the LAD territory, and our results could not be extrapolated to other arteries, for which the feasibility of noninvasive CFR is lower than for LAD.21 Hyperemia was induced differently for FFR and CFR, by intracoronary adenosine and intravenous adenosine, respectively. However, several studies have demonstrated the equivalence between these two methods for obtaining maximal achievable hyperemia, particularly with high intracoronary doses.12,29,30 The use of an FFR cutoff value of 0.80 as reflecting a significant lesion is debatable given that previous studies, in a variety of clinical and angiographic conditions, used FFR cutoff values of 0.75 to 0.80.4,5,8,15-17,23 However, very few patients in our study had FFR in the ‘‘gray zone’’ (n = 4), and the use of a cutoff of 0.75 would not have influenced our main results. Furthermore, a recent multicenter study in patients with multivessel lesions demonstrated the usefulness of the cutoff of 0.80.4 The incidence of significant lesions based on FFR <0.80 was relatively low (26%) in our study compared with previous studies (35% in the DEFER and Fractional Flow Reserve Versus Angiography for Multivessel Evaluation studies),8,31 in which the populations were quite different. Nonetheless, our results need confirmation with a larger study involving more functionally significant lesions. Finally, because CFR measures a diastolic event, the comparison with diastolic FFR would have been more attractive, but this latter tool is more complex to obtain than the mean FFR.
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CONCLUSIONS In patients with LAD stenoses of intermediate severity, discordant results between noninvasive CFR and FFR were not unusual, and not surprisingly, the anatomic determinants of the stenosis severity were better correlated with FFR than with CFR. However, CFR, which is a global evaluation of the coronary tree, had a very high sensitivity to detect a nonsignificant lesion, despite the high prevalence of vascular risk factors. Therefore, CFR is suitable in routine clinical practice for the evaluation of intermediate lesions and the follow-up of those treated medically, with the advantages of being totally noninvasive, easily available at bedside, at low cost, with no radiation exposure, subjective readings, or sophisticated rules. If CFR is >2, there is a high likelihood of a nonsignificant lesion with an FFR >0.8.
REFERENCES 1. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995;92:2333-42. 2. White CW, Wright CB, Doty DB, Hiratza LF, Eastham CL, Harrison DG, et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984;310: 819-24. 3. Fischer JJ, Samady H, McPherson JA, Sarembock IJ, Powers ER, Gimple LW, et al. Comparison between visual assessment and quantitative angiography versus fractional flow reserve for native coronary narrowings of moderate severity. Am J Cardiol 2002;90:210-5. 4. Tonino PAL, De Bruyne B, Pijls NHJ, Siebert U, Ikeno F, van’t Veer M, et al., for the FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24. 5. Pijls NHJ, De Bruyne B, Peels K, Van der Vort PH, Bonnier HJ, Bartunek J, et al. Measurement of fractional flow reserve to assess the functional severity of coronary artery stenoses. N Engl J Med 1996;334:1703-8. 6. Meimoun P, Benali T, Sayah S, Luycx-Bore A, Boulanger J, Zemir H, et al. Evaluation of left anterior descending coronary artery stenosis of intermediate severity using transthoracic coronary flow reserve and dobutamine stress echocardiography. J Am Soc Echocardiog 2005;12:1233-40. 7. Okayama H, Sumimoto T, Hiasa G, Nishimura K, Morioka N, Yamamoto K, et al. Assessment of intermediate stenosis in the left anterior descending coronary artery with contrast-enhanced transthoracic Doppler echocardiography. Coron Artery Dis 2003;14:247-54. 8. Pijls NHJ, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van’t Veer M, et al. Percutaneous coronary intervention of functionally non significant stenosis: 5-year follow-up of the DEFER study. J Am Coll Cardiol 2007;49:2105-13. 9. Meimoun P, Benali T, Elmkies F, Sayah S, Luycx-Bore A, Doutrelan L, et al. Prognostic value of transthoracic coronary flow reserve in medically treated patients with proximal left anterior descending artery stenosis of intermediate severity. Eur J Echocardiogr 2009;10:127-32. 10. Rigo F, Sicari R, Gherardi S, Djordjevic-Dikic A, Cortigiani L, Picano E. Prognostic value of coronary flow reserve in medically treated patients with left anterior descending coronary disease with stenosis 51% to 75% in diameter. Am J Cardiol 2007;100:1527-31. 11. D’Andrea A, Severino S, Mita C, Riegler L, Cocchia R, Gravino R, et al. Clinical outcome in patients with intermediate stenosis of left anterior descending coronary artery after deferral of revascularization on the basis of noninvasive coronary flow reserve measurement. Echocardiography 2009;26:431-40. 12. Casella G, Leibig M, Schiele M, Schrepf R, Seelig V, Stempfle AU, et al. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J 2004;148:590-5.
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13. Meimoun P, Malaquin D, Benali T, Boulanger J, Zemir H, Sayah S, et al. Non invasive coronary flow reserve after successful primary angioplasty for acute anterior myocardial infarction is an independent predictor of left ventricular recovery and in-hospital cardiac events. J Am Soc Echocardiogr 2009;22:1071-9. 14. Meimoun P, Sayah S, Tcheuffa JC, Benali T, Luycx-Bore A, Levy F, et al. Transthoracic coronary flow velocity reserve assessment: comparison between adenosine and dobutamine. J Am Soc Echocardiogr 2006;19: 1220-8. 15. Meuwissen M, Chamuleau SAJ, Siebes M, Schotborgh CE, Koch KT, de Winter RJ, et al. Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions. Circulation 2001;103:184-7. 16. Meuwissen M, Siebes M, Chamuleau SAJ, Van Eck-Smit BLF, Koch KT, De Winter RJ, et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation 2002;106:441-6. 17. Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, et al. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Circulation 2006;114: 1321-41. 18. Matsumara Y, Hozumi T, Watanabe H, Fujimoto K, Sugioka K, Takemoto Y, et al. Cut-off value of coronary flow velocity reserve by transthoracic Doppler echocardiography for diagnosis of significant left anterior descending artery stenosis in patients with coronary risk factors. Am J Cardiol 2003;92:1389-93. 19. Hozumi T, Yoshida K, Akasaka T, Asami Y, Ogata Y, Takagi T, et al. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique. J Am Coll Cardiol 1998;32:1251-60. 20. Caiati C, Montaldo C, Zedda N, Montisci R, Ruscazio M, Lai G, et al. Validation of a non-invasive method (contrast enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire. J Am Coll Cardiol 1999;34:1193-200. 21. Meimoun P, Tribouilloy C. Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography: a magic tool for the real world. Eur J Echocardiogr 2008;9:449-57. 22. Dini FL, Ghiadoni L, Conti U, Stea F, Buralli S, Taddei S, et al. Coronary flow reserve in idiopathic dilated cardiomyopathy: relation with left ventricular wall stress, natriuretic peptides, and endothelial dysfunction. J Am Soc Echocardiogr 2009;22:354-60. 23. Kini AS, Kim MC, Moreno PR, Krishnan P, Ivan OC, Sharma SK. Comparison of coronary flow reserve and fractional flow reserve in patients with versus without diabetes mellitus and having elective percutaneous coronary intervention and abciximab therapy (from the PREDICT trial). Am J Cardiol 2008;101:796-800. 24. Kern MJ, Samady H. Current concepts of integrated coronary physiology in the catheterization laboratory. J Am Coll Cardiol 2010;55: 173-85. 25. Kern MJ, Donohue TJ, Aguirre FV, Bach RG, Caracciolo EA, Wolford T, et al. Clinical outcome of deferring angioplasty in patients with normal translesional pressure-flow velocity measurements. J Am Coll Cardiol 1995;25:178-87. 26. Ferrari M, Schnell B, Werner GS, Figulla HR. Safety of deferring angioplasty in patients with normal coronary flow velocity reserve. J Am Coll Cardiol 1999;33:83-7. 27. Chamuleau SAJ, Tio RA, de Cook CC, de Muinck ED, Pijls NH, van EckSmit BL, et al. Prognostic value of coronary blood flow velocity and myocardial perfusion in intermediate coronary narrowings and multivessel disease. J Am Coll Cardiol 2002;39:852-8. 28. Barbato E, Aarnoudse W, Aengevaeren WR, Werner G, Klauss V, Bojara W, et al. Validation of coronary flow reserve measurements by thermodilution in clinical practice. Eur Heart J 2004;25:219-23.
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29. Jeremias A, Whitbourn RJ, Filardo SD, Fitzgerald PJ, Cohen DJ, Tuzcu M, et al. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Am Heart J 2000;140:651-7. 30. De Bryune B, Pijls N, Barbato E, Bartunek J, Bech JW, Wijns W, et al. Intracoronary and intravenous adenosine 50 -triphosphate, adenosine, papaver-
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ine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003;107:1877-83. 31. Tonino PAL, Fearon WF, De Bryune B, Oldroyd KG, Leesar MA, Ver Lee PN, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study. J Am Coll Cardiol 2010;55: 2816-21.
Background: Assessment of the functional significance of left anterior descending coronary artery (LAD) stenosis of intermediate severity (50%–70% diameter stenosis) is challenging. The aim of this study was to compare the value of noninvasive coronary flow reserve (CFR) with that of invasive fractional flow reserve (FFR) in the setting of LAD stenosis of angiographic intermediate severity. Methods: Fifty stable consecutive patients (mean age, 63 6 13 years; 11 women; mean left ventricular ejection fraction, 61 6 10%) with angiographic proximal LAD stenoses of intermediate severity (55.5 6 5% diameter stenosis on quantitative coronary angiography), no previous anterior myocardial infarction, and various vascular risk factors were prospectively studied. They underwent FFR assessment with intracoronary bolus adenosine (150 mg), and CFR assessment using intravenous adenosine (140 mg/kg/min over 2 min) in the distal part of the LAD on the same day in nearly all patients. CFR was defined as hyperemic peak diastolic LAD flow velocity divided by baseline flow velocity (normal value >2), and FFR was defined as distal pressure divided by mean aortic pressure during maximal hyperemia (normal value >0.8). Results: The mean FFR and CFR were 0.84 6 0.07 and 2.7 6 0.75, respectively, in the whole population. Concordant results between FFR and CFR were seen in 44 patients (88%) and discordant results in six patients (12%). There was a significant correlation between CFR and FFR (r = 0.59, P < .01). A better correlation was found between FFR and percentage LAD diameter stenosis, and lesion length (all P values < .05), than between CFR and the same anatomic markers of stenosis severity (all P values = NS). The sensitivity, specificity, and positive and negative predictive values of CFR >2 to detect a nonsignificant lesion defined by normal FFR were 95%, 69%, 90%, and 82%, respectively. Conclusions: In patients with LAD stenosis of intermediate severity, discordant results between noninvasive CFR and FFR were not unusual, and the anatomic determinants of the stenosis were better correlated to FFR than to CFR. However, CFR, which is a global evaluation of the coronary tree, has very high sensitivity to detect a nonsignificant lesion, despite the high prevalence of vascular risk factors. (J Am Soc Echocardiogr 2011;24:374-81.) Keywords: Coronary flow reserve, Fractional flow reserve, Intermediate coronary stenosis, Doppler echocardiography
The physiologic significance of coronary stenosis of intermediate severity on angiography is important for clinical decision making but is difficult to assess.1-4 Coronary angiography alone cannot accurately predict the significance of most intermediate stenoses. In this setting, there is a poor correlation with stress testing to predict the functional significance of stenosis and high interobserver variability in evaluating gne Hospital, From the Department of Cardiology and Intensive Care Unit, Compie gne, France. Compie Reprint requests: Patrick Meimoun, MD, Department of Cardiology and Intensive Care Unit, Centre Hospitalier de Compiegne, 8 rue Henri Adnot, 60200 gne, France (E-mail: [email protected]). Compie 0894-7317/$36.00 Copyright 2011 by the American Society of Echocardiography. doi:10.1016/j.echo.2010.12.007
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coronary stenosis severity on the basis of angiography alone.1-6 Therefore, according to the discordance between anatomy and function, proof that a stenosis is functionally significant is needed before attempting revascularization in this setting.1-7 Fractional flow reserve (FFR), available in the catheterization laboratory, is well recognized as the gold standard to evaluate these stenoses.4,5 On the basis of the measurement of the translesional pressure gradient during hyperemia, this tool assesses accurately the physiologic significance of a stenosis, and recent studies have demonstrated its important prognostic value.4,8 However, FFR is not available in all catheterization laboratories, and given its invasive nature, it is not suitable for the potential follow-up of stenoses treated medically, which may progress and become significant. Coronary flow reserve (CFR) measured by transthoracic Doppler echocardiography is a very attractive tool for the assessment of coronary
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stenoses of intermediate severity. It allows the noninvasive evaluaCFR = Coronary flow reserve tion of a stenosis at bedside and also provides prognostic value in FFR = Fractional flow reserve this setting.6,7,9-11 However, CFR LAD = Left anterior is a global evaluation of the descending coronary artery coronary tree theoretically limited by concomitant illnesses affecting the coronary microcirculation, which is not the case for FFR. Furthermore, in daily clinical practice, patients with intermediate coronary stenoses have various vascular risk factors that could influence the coronary microcirculation and affect CFR. A direct comparison of FFR and noninvasive CFR has never been performed, particularly in the setting of coronary stenoses of intermediate severity. Therefore. our objective was to assess the reliability of noninvasive CFR in comparison with FFR in the same group of stable patients with left anterior descending coronary artery (LAD) stenoses of angiographic intermediate severity. Abbreviations
METHODS Fifty consecutive patients admitted to our institution for diagnostic coronary angiography who had LAD stenoses of angiographic intermediate severity (50%–70%) prospectively underwent FFR and CFR to assess the functional significance of the stenoses for which the angiographer was unable to make a decision regarding revascularization based solely on the angiogram because stress testing was not performed, was inconclusive, or was ambiguous in most cases. CFR and FFR were performed the same day in the majority of patients (n = 42), in random order, and between 2 days and 1 week apart in the remainder of patients (n = 8) for logistic reasons. The reasons for coronary angiography were as follows: acute coronary syndromes involving arteries other than the LAD (n = 14), chest pain with positive or inconclusive exercise electrocardiographic or stress testing results (n = 19) or without documented ischemia (n = 6), suggestion of restenosis after angioplasty (n = 3), heart failure assessment (n = 5), and other (n = 3). Among the patients who underwent myocardial perfusion imaging or stress echocardiography (n =10), nine were considered to have ischemia, five in territories not matching the LAD territory and four in the LAD territory. Exclusion criteria were previous anterior myocardial infarction and acute coronary syndromes involving the LAD, stenosis in the distal part of the LAD, severe valvular disease, and contraindication to adenosine (asthma, high-degree atrioventricular block). Patients with acute coronary syndromes involving arteries other than the LAD could be included in the study if successful percutaneous coronary angioplasty was performed in all patients $2 weeks previously. All patients were in stable sinus rhythm and continued their cardiac medications at the time of FFR and CFR. They all presented with stable coronary artery disease at the time of the tests. Inform consent was obtained from all patients. Coronary Angiography Selective coronary angiography was performed using standard techniques via the femoral or radial approach. The severity of coronary stenosis was evaluated by multiple projections and was determined by experienced investigators with commercially available quantitative coronary angiographic software program (Integris HM 3000; Philips Medical Systems, Andover, MA). Using the guiding catheter as a scaling device, reference diameter, minimal luminal diameter, and percentage diameter stenosis were calculated.
FFR Coronary pressure was measured with a commercially 0.014-inch pressure monitoring guidewire (PrimeWire; Volcano Corporation, San Diego, CA). The wire was introduced through a 6Fr or 7Fr guiding catheter, calibrated, advanced into the coronary artery, and positioned about 3 cm distal to the stenosis. Mean aortic and distal pressure were measured at baseline and during an intracoronary bolus of 150 mg adenosine.12 FFR was defined as previously described4,5 as the ratio of mean hyperemic distal coronary pressure measured using the pressure wire to mean aortic pressure measured using the guiding catheter during maximal hyperemia. An abnormal value of FFR was defined as <0.8.4 Heart rate, distal pressure, and aortic pressure were continuously recorded and digitally stored during the procedure. Final values of FFR represented an average value of three cardiac cycles. CFR Noninvasive CFR was performed with commercially available machines (Acuson Sequoia 256, Siemens Medical Solutions, USA, Inc., Mountain View, CA; and Vivid E9, GE Healthcare, Milwaukee, WI) as previously described.13,14 Briefly, CFR was assessed in the distal part of the LAD using a low multifrequency transducer (3V2C or M5S probe), downstream to the LAD stenosis in all cases. Visualization of the artery was performed with color Doppler flow mapping guidance. For color Doppler echocardiography, the velocity range was set in the range of 12 to 19 cm/sec. Blood flow velocity was measured by pulsed-wave Doppler echocardiography using a sample volume of 3 to 4 mm placed on the color signal in the distal LAD. Noninvasive CFR was measured during intravenous infusion of adenosine (0.14 mg/kg/min over 2 min). Blood flow velocity measurements were performed offline by an experienced investigator who was blinded to the patient data by contouring the spectral Doppler signals using the integrated software package of the ultrasound system. CFR was calculated as the ratio of hyperemic to basal peak diastolic flow velocities. Final values of flow velocity represented an average of three cardiac cycles. The electrocardiogram was monitored continuously throughout adenosine infusion. Blood pressure and heart rate were measured at baseline and at the time of peak action of adenosine. An abnormal value of CFR was defined as <2.6,7,9-11,15-18 To improve visualization of the color Doppler signal and/or to obtain clear spectral Doppler signals in the LAD, a contrast agent was used in seven patients (14%) (SonoVue; Bracco, Milan, Italy) and administrated intravenously as a 0.1-mL bolus. The interobserver and intraobserver variability for CFR measurements in our experience have been previously reported (about 4%).6,14 Statistical Analysis Results are expressed as mean 6 SD and percentages. Categorical variables were compared using c2 analysis or Fisher’s exact test as appropriate, and continuous variables were compared using Student’s t test for paired or unpaired data. The relationships between FFR, CFR, percentage LAD diameter stenosis, percentage LAD area stenosis, and lesion length were evaluated using linear and nonlinear correlations, and those exhibiting the best fit were retained. Statistical analysis was performed using MedCalc for Windows version 10.6.0.0 (MedCalc Software, Mariakerke, Belgium). P values < .05 were considered significant.
RESULTS Baseline characteristics of the study population are listed in Table 1. The mean age was 63 6 13 years, with 11 women (22%).
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Table 1 Baseline characteristics (n = 50) Variable
Table 3 Doppler echocardiographic characteristics (n = 50) Value
Age (y) Women/men BMI (kg/m2) Diabetes Hypertension Smoking Dyslipidemia b-blockers Aspirin Statins ACE inhibitors/ARBs Clopidogrel Previous MI Previous PCI
63 6 13 11/39 27.5 6 4.5 9 (18%) 27 (54%) 15 (30%) 35 (70%) 42 (84%) 49 (98%) 45 (90%) 39 (78%) 41 (82%) 12 (24%) 28 (56%)
Data are expressed as mean 6 SD or as number (percentage). ACE, Angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BMI, body mass index; MI, myocardial infarction; PCI, percutaneous coronary intervention.
Table 2 Angiographic data (n = 50) Variable
Value
Minimal luminal diameter (mm) Reference luminal diameter (mm) Percentage LAD stenosis (%) Lesion length (mm) Percentage area stenosis (%) Proximal LAD/mid-LAD FFR FFR <0.8 Type of stenosis A B1 B2 C Baseline systolic blood pressure (mm Hg) Baseline diastolic blood pressure (mm Hg) Baseline heart rate (beats/min) Baseline RPP (mm Hg $ beats/min $ 103)
1.34 6 0.32 3.01 6 0.59 55.5 6 5 14.1 6 6.5 79.9 6 4.7 26 (52%)/24 (48%) 0.84 6 0.08 13 (26%) 2 (4%) 16 (32%) 24 (48%) 8 (16%) 128 6 22 76 6 8 67 6 11 8.6 6 2.4
Data are expressed as mean 6 SD or as number (percentage). RPP, Rate-pressure product.
Histories of posterior-inferior myocardial infarction were seen in 12 patients (24%), and 28 patients (56%) underwent previous angioplasty. Both tests were well tolerated, with no serious adverse events. Angiographic and Doppler echocardiographic parameters are summarized in Tables 2 and 3, respectively. No significant differences were seen among hemodynamic data between the two exams (all P values = NS). The mean percentage LAD stenosis was 55.5 6 5%. All patients had successful CFR evaluations, with the help of a contrast agent in 14%. The mean CFR was 2.7 6 0.75 (range, 1.3–4.4), and the mean FFR was 0.84 6 0.07 (range, 0.65–0.98). An illustrative case is depicted in Figure 1.
Variable
Value
Baseline LAD flow velocity (cm/sec) Hyperemic LAD flow velocity (cm/sec) CFR CFR <2, n (%) Baseline heart rate (beats/min) Baseline systolic blood pressure (mm Hg) Baseline diastolic blood pressure (mm Hg) Baseline RPP (mm Hg $ beats/min $ 103) LV ejection fraction (%) LV mass index (g/m2) E/Ea ratio PASP (mm Hg)
27 6 7 70.5 6 19 2.7 6 0.75 11 (22%) 65 6 12 133 6 21 70 6 11 8.6 6 2.2 61 6 10 91 6 19 8.5 6 5 30 6 7
Data are expressed as mean 6 SD or as number (percentage). LV, Left ventricular; PASP, pulmonary artery systolic pressure; RPP, rate-pressure product.
Correlations There was a weak but significant correlation between CFR and FFR (r = 0.59, P < .01; Figure 2). Better correlations were found between FFR and percentage LAD diameter stenosis, percentage LAD area stenosis, and lesion length (all P values < .05) than between CFR and the same anatomic markers of stenosis severity (all P values = NS) (see Figure 3). FFR and CFR Above and Below the Threshold Values Patients with low CFR (n = 11) were more frequently diabetics (45% vs 10%, P = .02), had lower left ventricular ejection fractions (P < .05), had lower FFR (0.74 6 0.06 vs 0.86 6 0.05, P < .001), and had higher percentage LAD diameter stenoses (58.6 6 7% vs 54.6 6 5%, P = .03) than patients with CFR >2, whereas other demographic, hemodynamic, Doppler echocardiographic, and angiographic variables did not differ significantly between these subgroups (all P values = NS). Compared with patients with FFR >0.8, those with low FFR were more frequently diabetics (45% vs 10%, P = .02), had higher percentage LAD diameter stenoses (60.6 6 7% vs 54 6 4%, P = .01) and percentage LAD area stenoses (P = .05), had lower CFR (2.2 6 0.7 vs 2.9 6 0.7, P < .01), and showed a trend toward longer lesion length (P = .08). Discordant and Concordant Results Among the 37 patients who had FFR >0.8, 35 had CFR >2, and among the 13 patients with FFR #0.8, nine had CFR #2 (see Figure 2). Therefore, the sensitivity, specificity, and positive and negative predictive values for CFR to detect a nonsignificant lesion (defined as FFR >0.8) were 95.5%, 69%, 90%, and 82%, respectively, with an accuracy of 88%.
DISCUSSION Noninvasive CFR has already been compared with various tools, such as angiography,18 invasive Doppler flow wire,19,20 nuclear cardiac imaging,7 and stress echocardiography,6,10 but curiously, no specific data are available on noninvasive CFR and FFR. A few studies have compared invasive CFR with FFR in patients with intermediate
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Figure 1 Illustrative case. A 70-year old man with chest pain and inconclusive stress test results. (Bottom right) Coronary angiography showed a long 50% mid-LAD stenosis. (Top) FFR was 0.86. (Bottom left) Noninvasive CFR was concordant with a mean value at 2.9 (basal and hyperemic flow velocities are depicted, demonstrating a biphasic pattern with diastolic predominance). stenoses,15,16 but to our knowledge, ours is the first to compare noninvasive CFR with FFR, the method of choice for the functional evaluation of a coronary stenosis. FFR is a measure of a pressure gradient across a coronary stenosis during hyperemia, regardless of the flow that passes through the stenosis, or of microvascular resistance, whereas CFR is the ratio of hyperemic coronary flow relative to baseline, regardless of the concomitant pressure gradient across the stenosis. However, there is a curvilinear relationship between the pressure drop across a stenosis and coronary flow, and dealing with only one of the components could lead to missing data about the stenosis properties. Despite these limitations, FFR has several advantages over other techniques for the evaluation of stenosis severity, including its specificity to epicardial lesions, independence from hemodynamic alterations, and high spatial resolution and reproducibility.4,5,17 By contrast, CFR is influenced by hemodynamics and the coronary microcirculation.17,21 Hyperemic flow, which is linearly related to coronary perfusion pressure, depends on total coronary resistance (epicardial vessel, small arteries, arterioles, and intramyocardial capillary system), whereas baseline flow is influenced by several factors, including myocardial oxygen demand and vasomotor tone. Other factors influence CFR, such as aging, left ventricular mass, drugs, habits, sexual hormones, and left ventricular end-diastolic wall stress.17,21,22 Therefore, when one would assess the functional significance of an epicardial coronary stenosis using CFR, one should be aware of all these influencing factors when interpreting the results. Given these considerations, it is not surprising to find that the anatomic determinants of stenosis severity, such as percentage LAD
Figure 2 Scatterplot of the curvilinear relationship between noninvasive CFR and FFR. Horizontal and vertical dashed lines are depicted at the set points of CFR of 2 and FFR of 0.8, respectively, to show the limit between normal and abnormal values.
diameter stenosis, lesion length, and percentage LAD area stenosis, were significantly correlated with FFR but not CFR in these intermediate stenoses. Despite these drawbacks, the use of CFR in this study demonstrated good accuracy to detect a nonsignificant lesion in comparison with FFR. Indeed, in 88% of cases,
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Figure 3 Relationship between the anatomic determinants of the stenosis and CFR and FFR. (A) Percentage LAD diameter stenosis. (B) Percentage area stenosis. (C) Lesion length. noninvasive CFR assessment of the LAD matched with invasive FFR, which matched well with invasive angiography. Diabetes was associated with both impaired CFR and FFR in this study, high-
lighting the negative impact of this disease on the whole coronary tree, as shown recently in patients with acute myocardial infarction.23
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Prognostic Value of CFR and FFR Several studies have demonstrated the prognostic value of FFR in patients with intermediate coronary stenosis.24 A revascularization of a lesion with FFR >0.75 to 0.8 can safely be deferred for up to 5 years.8 However, on an individual basis, close follow-up is mandatory for patients with functionally nonsignificant stenoses treated medically. A noninvasive test such as CFR could be useful in this setting to detect a progression of disease. Few studies also showed the prognostic value of invasive25-27 and noninvasive CFR9-11 in patients with intermediate stenosis, but a direct comparison between noninvasive CFR and FFR is lacking. Comparison of CFR and FFR Discordant results between CFR and FFR were found in six patients (12%), which is rather low compared with the 27% found in an invasive study.15 The different methodologies and populations studied may partially account for these differences. In this study, an invasive Doppler flow wire was used to assess CFR in a group of 126 patients with stable angina, with 150 intermediate coronary stenoses between 40% and 70% by visual assessment, and the cutoff value of normal FFR was lower (0.75), as was the intracoronary dose of adenosine used. Seventeen percent of lesions had normal CFR and low FFR, and 10% had low CFR and normal FFR. This latter group was characterized by a higher hyperemic vascular resistance and baseline flow, whereas the former group had a higher diameter stenosis. Indeed, when taking into account both the pressure gradient and the flow across the stenosis during hyperemia, the accuracy to detect reversible defect with nuclear cardiac imaging is higher than when using CFR or FFR alone (87% vs 75%).16 In addition, noninvasive CFR differs slightly from invasive CFR using a Doppler flow wire: the angle between the Doppler beam and the artery is more pronounced, and the systolic component of the flow is not usually used for CFR calculation with the noninvasive method, and the site of flow velocity measurement is not necessarily the same. Despite these differences, the correlation between CFR and FFR are quite similar, 0.59 in our study and 0.6 in the invasive study cited above.15 Because CFR interrogates the entire coronary system, including both the conduit and the resistive vessels, and because FFR is an evaluation of the epicardial coronary tree, the patients with low CFR (<2) and ‘‘normal’’ FFR (>0.8) could be interpreted as patients with mainly coronary microvascular impairment. However, despite the prevalence of a substantial proportion of various vascular risk factors, which could also affect the microcirculation, in our population, the sensitivity for CFR to detect a nonsignificant lesion, defined as FFR >0.8, was very high (95%). Noninvasive CFR using a cutoff value of 2 also detects with good precision significant LAD stenosis by angiography in a wide range of stenosis severity, despite a high potential for coronary microvascular impairment.18 The high dose of intracoronary adenosine used in our study reduces the likelihood of insufficient hyperemia for FFR evaluation12 as another explanation for this discrepancy. Patients with low FFR and ‘‘normal’’ CFR were not frequently seen in our study (n = 4 [8%]), and several hypothesis might explain these discrepancies. On the basis of previous results and according to the ischemic threshold, a normal value of CFR was defined as >2.6,911,15-18 Unlike FFR, which has a universal normal value of 1, one can speculate that CFR does not have the same normal value in every patient, and it could be much higher in some patients with low FFR and CFR >2. Interestingly, noninvasive CFR improved significantly within 24 hours after angioplasty in two patients with low FFR and ‘‘normal’’ CFR (from 2.6 to 3.4 and 3.6, respectively).
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Another reason for explaining this divergence is provided by the variability of microvascular resistance, which influences FFR and CFR in opposite directions, particularly in the setting of intermediate stenoses.15,16 Indeed, distal pressure depends on flow across the stenosis, which is determined by both epicardial and microvascular resistance.15 For a given epicardial stenosis resistance, a change in microvascular resistance affects distal pressure and flow in opposite directions. In other words, when there is a low microvascular resistance at hyperemia, the flow across the stenosis increases, distal pressure decreases, and therefore FFR will be lower. In contrast, CFR is preserved. Finally, one limitation of the noninvasive evaluation of CFR on LAD is the possibility of the interrogation of a well-developed, nonstenotic diagonal branch that runs in parallel with the LAD. The consequence will be normal CFR in the interrogated vessel and low FFR in the LAD. However, this situation is rare in our experience, and septal branches when visible could unambiguously detect the LAD by color Doppler flow interrogation. Furthermore, if the sampling site of the coronary flow is proximal to the stenosis, CFR may be normal, as there are side branches between the sampling site and the stenosis, which reflects perfusion in normal territories. To avoid this situation, distal stenoses were exclusion criteria, and careful attention was made to measure the flow at the distal part of the LAD, downstream to the stenosis. Because CFR is a noninvasive evaluation, technical limitations could also explain the discordant results between CFR and FFR, such as a poor signal, poor technical acquisition (limited by the use of a contrast agent), or some measuring variability. Limitations Coronary thermodilution-derived CFR has been developed in recent years and permits the simultaneous assessment of CFR and FFR using a single coronary pressure wire.28 However, this technique is not available in our catheterization lab, and our goal was to compare noninvasive CFR and FFR to validate the noninvasive evaluation of intermediate stenoses against FFR. We compared noninvasive CFR with FFR in the LAD territory, and our results could not be extrapolated to other arteries, for which the feasibility of noninvasive CFR is lower than for LAD.21 Hyperemia was induced differently for FFR and CFR, by intracoronary adenosine and intravenous adenosine, respectively. However, several studies have demonstrated the equivalence between these two methods for obtaining maximal achievable hyperemia, particularly with high intracoronary doses.12,29,30 The use of an FFR cutoff value of 0.80 as reflecting a significant lesion is debatable given that previous studies, in a variety of clinical and angiographic conditions, used FFR cutoff values of 0.75 to 0.80.4,5,8,15-17,23 However, very few patients in our study had FFR in the ‘‘gray zone’’ (n = 4), and the use of a cutoff of 0.75 would not have influenced our main results. Furthermore, a recent multicenter study in patients with multivessel lesions demonstrated the usefulness of the cutoff of 0.80.4 The incidence of significant lesions based on FFR <0.80 was relatively low (26%) in our study compared with previous studies (35% in the DEFER and Fractional Flow Reserve Versus Angiography for Multivessel Evaluation studies),8,31 in which the populations were quite different. Nonetheless, our results need confirmation with a larger study involving more functionally significant lesions. Finally, because CFR measures a diastolic event, the comparison with diastolic FFR would have been more attractive, but this latter tool is more complex to obtain than the mean FFR.
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CONCLUSIONS In patients with LAD stenoses of intermediate severity, discordant results between noninvasive CFR and FFR were not unusual, and not surprisingly, the anatomic determinants of the stenosis severity were better correlated with FFR than with CFR. However, CFR, which is a global evaluation of the coronary tree, had a very high sensitivity to detect a nonsignificant lesion, despite the high prevalence of vascular risk factors. Therefore, CFR is suitable in routine clinical practice for the evaluation of intermediate lesions and the follow-up of those treated medically, with the advantages of being totally noninvasive, easily available at bedside, at low cost, with no radiation exposure, subjective readings, or sophisticated rules. If CFR is >2, there is a high likelihood of a nonsignificant lesion with an FFR >0.8.
REFERENCES 1. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995;92:2333-42. 2. White CW, Wright CB, Doty DB, Hiratza LF, Eastham CL, Harrison DG, et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984;310: 819-24. 3. Fischer JJ, Samady H, McPherson JA, Sarembock IJ, Powers ER, Gimple LW, et al. Comparison between visual assessment and quantitative angiography versus fractional flow reserve for native coronary narrowings of moderate severity. Am J Cardiol 2002;90:210-5. 4. Tonino PAL, De Bruyne B, Pijls NHJ, Siebert U, Ikeno F, van’t Veer M, et al., for the FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24. 5. Pijls NHJ, De Bruyne B, Peels K, Van der Vort PH, Bonnier HJ, Bartunek J, et al. Measurement of fractional flow reserve to assess the functional severity of coronary artery stenoses. N Engl J Med 1996;334:1703-8. 6. Meimoun P, Benali T, Sayah S, Luycx-Bore A, Boulanger J, Zemir H, et al. Evaluation of left anterior descending coronary artery stenosis of intermediate severity using transthoracic coronary flow reserve and dobutamine stress echocardiography. J Am Soc Echocardiog 2005;12:1233-40. 7. Okayama H, Sumimoto T, Hiasa G, Nishimura K, Morioka N, Yamamoto K, et al. Assessment of intermediate stenosis in the left anterior descending coronary artery with contrast-enhanced transthoracic Doppler echocardiography. Coron Artery Dis 2003;14:247-54. 8. Pijls NHJ, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van’t Veer M, et al. Percutaneous coronary intervention of functionally non significant stenosis: 5-year follow-up of the DEFER study. J Am Coll Cardiol 2007;49:2105-13. 9. Meimoun P, Benali T, Elmkies F, Sayah S, Luycx-Bore A, Doutrelan L, et al. Prognostic value of transthoracic coronary flow reserve in medically treated patients with proximal left anterior descending artery stenosis of intermediate severity. Eur J Echocardiogr 2009;10:127-32. 10. Rigo F, Sicari R, Gherardi S, Djordjevic-Dikic A, Cortigiani L, Picano E. Prognostic value of coronary flow reserve in medically treated patients with left anterior descending coronary disease with stenosis 51% to 75% in diameter. Am J Cardiol 2007;100:1527-31. 11. D’Andrea A, Severino S, Mita C, Riegler L, Cocchia R, Gravino R, et al. Clinical outcome in patients with intermediate stenosis of left anterior descending coronary artery after deferral of revascularization on the basis of noninvasive coronary flow reserve measurement. Echocardiography 2009;26:431-40. 12. Casella G, Leibig M, Schiele M, Schrepf R, Seelig V, Stempfle AU, et al. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J 2004;148:590-5.
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13. Meimoun P, Malaquin D, Benali T, Boulanger J, Zemir H, Sayah S, et al. Non invasive coronary flow reserve after successful primary angioplasty for acute anterior myocardial infarction is an independent predictor of left ventricular recovery and in-hospital cardiac events. J Am Soc Echocardiogr 2009;22:1071-9. 14. Meimoun P, Sayah S, Tcheuffa JC, Benali T, Luycx-Bore A, Levy F, et al. Transthoracic coronary flow velocity reserve assessment: comparison between adenosine and dobutamine. J Am Soc Echocardiogr 2006;19: 1220-8. 15. Meuwissen M, Chamuleau SAJ, Siebes M, Schotborgh CE, Koch KT, de Winter RJ, et al. Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions. Circulation 2001;103:184-7. 16. Meuwissen M, Siebes M, Chamuleau SAJ, Van Eck-Smit BLF, Koch KT, De Winter RJ, et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation 2002;106:441-6. 17. Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, et al. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Circulation 2006;114: 1321-41. 18. Matsumara Y, Hozumi T, Watanabe H, Fujimoto K, Sugioka K, Takemoto Y, et al. Cut-off value of coronary flow velocity reserve by transthoracic Doppler echocardiography for diagnosis of significant left anterior descending artery stenosis in patients with coronary risk factors. Am J Cardiol 2003;92:1389-93. 19. Hozumi T, Yoshida K, Akasaka T, Asami Y, Ogata Y, Takagi T, et al. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique. J Am Coll Cardiol 1998;32:1251-60. 20. Caiati C, Montaldo C, Zedda N, Montisci R, Ruscazio M, Lai G, et al. Validation of a non-invasive method (contrast enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire. J Am Coll Cardiol 1999;34:1193-200. 21. Meimoun P, Tribouilloy C. Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography: a magic tool for the real world. Eur J Echocardiogr 2008;9:449-57. 22. Dini FL, Ghiadoni L, Conti U, Stea F, Buralli S, Taddei S, et al. Coronary flow reserve in idiopathic dilated cardiomyopathy: relation with left ventricular wall stress, natriuretic peptides, and endothelial dysfunction. J Am Soc Echocardiogr 2009;22:354-60. 23. Kini AS, Kim MC, Moreno PR, Krishnan P, Ivan OC, Sharma SK. Comparison of coronary flow reserve and fractional flow reserve in patients with versus without diabetes mellitus and having elective percutaneous coronary intervention and abciximab therapy (from the PREDICT trial). Am J Cardiol 2008;101:796-800. 24. Kern MJ, Samady H. Current concepts of integrated coronary physiology in the catheterization laboratory. J Am Coll Cardiol 2010;55: 173-85. 25. Kern MJ, Donohue TJ, Aguirre FV, Bach RG, Caracciolo EA, Wolford T, et al. Clinical outcome of deferring angioplasty in patients with normal translesional pressure-flow velocity measurements. J Am Coll Cardiol 1995;25:178-87. 26. Ferrari M, Schnell B, Werner GS, Figulla HR. Safety of deferring angioplasty in patients with normal coronary flow velocity reserve. J Am Coll Cardiol 1999;33:83-7. 27. Chamuleau SAJ, Tio RA, de Cook CC, de Muinck ED, Pijls NH, van EckSmit BL, et al. Prognostic value of coronary blood flow velocity and myocardial perfusion in intermediate coronary narrowings and multivessel disease. J Am Coll Cardiol 2002;39:852-8. 28. Barbato E, Aarnoudse W, Aengevaeren WR, Werner G, Klauss V, Bojara W, et al. Validation of coronary flow reserve measurements by thermodilution in clinical practice. Eur Heart J 2004;25:219-23.
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29. Jeremias A, Whitbourn RJ, Filardo SD, Fitzgerald PJ, Cohen DJ, Tuzcu M, et al. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Am Heart J 2000;140:651-7. 30. De Bryune B, Pijls N, Barbato E, Bartunek J, Bech JW, Wijns W, et al. Intracoronary and intravenous adenosine 50 -triphosphate, adenosine, papaver-
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ine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003;107:1877-83. 31. Tonino PAL, Fearon WF, De Bryune B, Oldroyd KG, Leesar MA, Ver Lee PN, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study. J Am Coll Cardiol 2010;55: 2816-21.