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 ± 13 years; 11 women; mean left ventricular ejection fraction, 61 ± 10%) with angiographic proximal LAD stenoses of intermediate severity (55.5 ± 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 μg), and CFR assessment using intravenous adenosine (140 μg/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 ± 0.07 and 2.7 ± 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.
The physiologic significance of coronary stenosis of intermediate severity on angiography is important for clinical decision making but is difficult to assess. 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 coronary stenosis severity on the basis of angiography alone. Therefore, according to the discordance between anatomy and function, proof that a stenosis is functionally significant is needed before attempting revascularization in this setting.
Fractional flow reserve (FFR), available in the catheterization laboratory, is well recognized as the gold standard to evaluate these stenoses. 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. 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 stenoses of intermediate severity. It allows the noninvasive evaluation of a stenosis at bedside and also provides prognostic value in this setting. However, CFR is a global evaluation of the 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.
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 μg adenosine. FFR was defined as previously described 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. 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. 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. 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%).
Statistical Analysis
Results are expressed as mean ± SD and percentages. Categorical variables were compared using χ 2 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 ± 13 years, with 11 women (22%). 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 ± 5%. All patients had successful CFR evaluations, with the help of a contrast agent in 14%. The mean CFR was 2.7 ± 0.75 (range, 1.3–4.4), and the mean FFR was 0.84 ± 0.07 (range, 0.65–0.98). An illustrative case is depicted in Figure 1 .
| Variable | Value |
|---|---|
| Age (y) | 63 ± 13 |
| Women/men | 11/39 |
| BMI (kg/m 2 ) | 27.5 ± 4.5 |
| Diabetes | 9 (18%) |
| Hypertension | 27 (54%) |
| Smoking | 15 (30%) |
| Dyslipidemia | 35 (70%) |
| β-blockers | 42 (84%) |
| Aspirin | 49 (98%) |
| Statins | 45 (90%) |
| ACE inhibitors/ARBs | 39 (78%) |
| Clopidogrel | 41 (82%) |
| Previous MI | 12 (24%) |
| Previous PCI | 28 (56%) |
| Variable | Value |
|---|---|
| Minimal luminal diameter (mm) | 1.34 ± 0.32 |
| Reference luminal diameter (mm) | 3.01 ± 0.59 |
| Percentage LAD stenosis (%) | 55.5 ± 5 |
| Lesion length (mm) | 14.1 ± 6.5 |
| Percentage area stenosis (%) | 79.9 ± 4.7 |
| Proximal LAD/mid-LAD | 26 (52%)/24 (48%) |
| FFR | 0.84 ± 0.08 |
| FFR <0.8 | 13 (26%) |
| Type of stenosis | |
| A | 2 (4%) |
| B1 | 16 (32%) |
| B2 | 24 (48%) |
| C | 8 (16%) |
| Baseline systolic blood pressure (mm Hg) | 128 ± 22 |
| Baseline diastolic blood pressure (mm Hg) | 76 ± 8 |
| Baseline heart rate (beats/min) | 67 ± 11 |
| Baseline RPP (mm Hg · beats/min · 10 3 ) | 8.6 ± 2.4 |
| Variable | Value |
|---|---|
| Baseline LAD flow velocity (cm/sec) | 27 ± 7 |
| Hyperemic LAD flow velocity (cm/sec) | 70.5 ± 19 |
| CFR | 2.7 ± 0.75 |
| CFR <2, n (%) | 11 (22%) |
| Baseline heart rate (beats/min) | 65 ± 12 |
| Baseline systolic blood pressure (mm Hg) | 133 ± 21 |
| Baseline diastolic blood pressure (mm Hg) | 70 ± 11 |
| Baseline RPP (mm Hg · beats/min · 10 3 ) | 8.6 ± 2.2 |
| LV ejection fraction (%) | 61 ± 10 |
| LV mass index (g/m 2 ) | 91 ± 19 |
| E/Ea ratio | 8.5 ± 5 |
| PASP (mm Hg) | 30 ± 7 |
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 ).
