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Myocardial Perfusion Reserve Assessed by T2-Prepared Steady-State Free Precession Blood Oxygen Level–Dependent Magnetic Resonance Imaging in Comparison to Fractional Flow Reserve Thomas Walcher, MD; Robert Manzke, PhD; Vinzenz Hombach, MD; Wolfgang Rottbauer, MD; Jochen Wöhrle, MD, FESC; Peter Bernhardt, MD, FACC Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 Background—Blood oxygen level–dependent (BOLD) cardiac magnetic resonance imaging (CMR) has been shown to be able to detect myocardial perfusion differences. However, validation of BOLD CMR against fractional flow reserve (FFR) is lacking. The aim of our study was to analyze the potential diagnostic accuracy of BOLD CMR in comparison to invasively measured FFR, which served as gold standard for a hemodynamic significant coronary lesion. Methods and Results—BOLD image was performed at rest and during adenosine infusion in a 1.5-T CMR scanner. Thirtysix patients were analyzed for relative BOLD signal intensity increase according to the 16-segment model. Invasive FFR measurements were performed in the 3 major coronary arteries during adenosine infusion in all patients. An FFR≤0.8 was regarded to indicate a significant coronary lesion. Relative BOLD signal intensity increase was significantly lower in myocardial segments supplied by coronary arteries with an FFR≤0.8 compared with segments with an FFR>0.8 (1.1±0.2 versus 1.5±0.2; P<0.0001). Sensitivity and specificity yielded 88.2% and 89.5%, respectively. Conclusions—CMR BOLD imaging reliably detects hemodynamic significant coronary artery disease and is, thus, an alternative to contrast–enhanced perfusion studies. (Circ Cardiovasc Imaging. 2012;5:580-586.) Key Words: blood oxygen level dependence ◼ cardiac magnetic resonance imaging ◼ coronary artery disease ◼ fractional flow reserve A blood flow.9 Furthermore, T2* BOLD CMR sequences can be used to image changes of myocardial oxygenation induced by dipyridamole as an indicator of myocardial ischemia.10 Recently, it has been shown that semiquantitative assessment of relative BOLD signal increase using a T2-prepared SSFP sequence highly correlates with the standard approach of contrast–enhanced perfusion CMR imaging.11 Myocardial perfusion assessed by the change in myocardial oxygenation with BOLD CMR has been correlated to quantitative coronary angiography.7,8 Fractional flow reserve (FFR) has been proposed for the physiological assessment of CAD to better characterize the clinical significance of coronary stenosis.12 It has been showed that FFR guided intervention significantly reduced mortality and myocardial infarction and is, thus, prognostically important.13 We compared a T2–prepared BOLD CMR sequence to FFR in patients with suspected CAD. ssessment of myocardial ischemia in patients with suspected coronary artery disease (CAD) is essential to guide further therapeutic strategy. Contrast–enhanced first-pass perfusion cardiac magnetic resonance imaging (CMR) during vasodilatation visualizes perfusion defects.1–5 However, high temporal and spatial resolution is required. Image artifacts as dark rim artifact can mistakenly be interpreted as perfusion defects.6 Furthermore, the use of exogenous contrast agents is required, which is especially an important issue in patients with severe renal failure. Clinical Perspective on p 586 Blood oxygen level–dependent (BOLD) CMR is based on the fact that oxyhemoglobin is slightly diamagnetic and deoxyhemoglobin paramagnetic resulting in the loss of T2* and T2, depending on tissue microvasculature and resulting blood volume. BOLD CMR, thus, uses an endogenous contrast without additional use of an exogenous contrast. Using a T2-prepared steady-state free precession (SSFP) BOLD CMR sequence, detection of myocardial ischemia in patients with CAD is possible.7,8 T2-prepared SSFP CMR has been shown to be related to blood oxygen saturation and coronary Methods Forty-two consecutive patients with stable angina pectoris and suspected CAD were prospectively included. All patients were referred for coronary angiography and had a previous positive or inconclusive stress test by the referring physician. Exclusion criteria were clinical Received November 30, 2011; accepted June 18, 2012. From the Department of Internal Medicine II, University of Ulm, Ulm, Germany (T.W., V.H., W.R., J.W., P.B.); and University of Applied Sciences, Kiel, Germany (R.M.). Correspondence to Peter Bernhardt, MD, Department of Internal Medicine II, University of Ulm, Albert-Einstein-Allee 23 89081 Ulm, Germany. E-mail [email protected] © 2012 American Heart Association, Inc. Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org 580 DOI: 10.1161/CIRCIMAGING.111.971507 Walcher et al BOLD MRI Compared With FFR 581 instability, known previous myocardial infarction, and contraindications for magnetic resonance imaging or adenosine infusion. For at least 24 hours before each CMR examination, methylxanthines were not allowed. All patients underwent coronary angiography within 1 week after CMR imaging. Morise risk score for CAD14 was calculated for each patient. The study was approved by the local ethics committee. All the participants gave written informed consent. CMR Imaging Protocol Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 Patients were examined in a 1.5-T whole-body scanner (Intera, Philips Medical Systems, Best, The Netherlands) using a 32-channel phased-array receiver coil (Philips Medical Systems). Heart rate, blood pressure, and oxygen saturation were noninvasively monitored. Functional imaging of the left ventricle was acquired using a SSFP sequence (repetition time, 3.4 ms; echo time, 1.7 ms; voxel size, 1.9×1.9 mm; flip angle α=55°; slice thickness, 8 mm; and no interslice gap) in contiguous short axis covering the entire left ventricle. The acquisition was performed in end-expiratory breath-hold with 40 phases per cardiac cycle. Slice thickness was 8 mm without interslice gap. For BOLD imaging a T2-prepared SSFP (repetition time, 2.6 ms; echo time, 1.3 ms; flip angle α=90°; voxel size, 1.7×1.7 mm; slice thickness, 8 mm; gap individually adjusted, T2 preparation time 40 ms with 4 refocusing pulses; and number of averages, 3) was acquired in 3 short axes (apical, midventricular, and basal), as previously reported.11 Typical breath-hold time was 6.8 second for a heart rate of 80 bpm. To ensure reproducibility of the 3 slices, 5 short axis from the mitral valve to the apex were planned and interslice gap was, thus, individually adjusted; the most apical and most basal slice were than deleted before image acquisition. After 3 minutes of adenosine infusion at a dosage of 140 µg/kg per minute, the BOLD sensitive sequence was repeated in the same orientation. CMR Image Analysis CMR images were analyzed in random order blinded to patients’ data and angiographic results. Functional images were analyzed for enddiastolic and end-systolic left ventricular volumes and ejection fractions were calculated. Image analysis of the BOLD sensitive images was performed using customized software developed by Matlab (TheMathoWorks, Inc, Natick, MA). Epicardial and endocardial borders were drawn manually in all short axes. The 3 acquired short axes were divided into segments according to the 16-segment model,15 and mean voxel intensities were calculated automatically for each myocardial segment.13 Mean signal intensity increase was calculated for each myocardial segment by subtraction of the signal intensity at rest from the signal intensity during vasodilatation, divided by the signal intensity at rest and multiplied by 100. Myocardial segments were assigned to the supplying coronary artery, as previously described.16 Figure 1 provides an example of BOLD imaging, color-encoded BOLD signal intensity increase and corresponding coronary angiogram. For further analysis of each coronary perfusion territory, the mean value of the 2 lowest scoring segments was used for further analysis. Cardiac Catheterization Cardiac catheterization was performed by the femoral approach using 5 or 6 F catheters within 7 days after CMR. FFR was measured with a coronary pressure guidewire (Radi Medical Systems) at a maximal hyperemia induced by intravenous adenosine. Infusion rate of adenosine at 140 µg/kg per minute was the same as during previous CMR examination. FFR was measured in the left anterior descending (LAD), circumflex artery (CX), and right coronary artery (RCA) after 3 minutes of intravenous adenosine infusion. FFR was calculated as the mean distal coronary pressure measured with the pressure wire, divided by the mean aortic pressure measured simultaneously with the guiding catheter during maximal hyperemia.16,17 An FFR value of ≤0.8 during adenosine infusion has been described to identify coronary stenoses causing ischemia with high accuracy.18–20 Based on these findings, we defined a cutoff FFR value as 0.8 in our study. FFR measurements served as reference standard for BOLD analysis. Statistical Analysis Data are reported as mean±SD. For categorical variables, the Fisher exact test was used to test differences between the FFR≤0.8 and FFR>0.8 groups. For continuous variables, we used a 2 tailed t test. P values in Figure 2 were calculated using t test. A P value <0.05 was considered statistically significant. The diagnostic performance of BOLD CMR was analyzed using receiver-operating characteristics (ROC) curve analyses. BOLD values were tested for normal distribution using the D’AgostinoPearson test. Interobserver and intraobserver correlation was performed in 10 patients using intraclass correlation coefficients. Correlation analysis was done using Pearson correlation. Logistic regression was performed to calculate χ2 values using the overall model fit. Figure 1. Blood oxygen level–dependent (BOLD) image examples in a midventricular short axis at rest (A) and during adenosine infusion (B) and color-encoded 16-segments BOLD signal intensity increase (C) in a patient with left anterior descending (LAD) stenosis (arrow) as seen on coronary angiogram (D). 582 Circ Cardiovasc Imaging September 2012 Figure 2. Box and whisker graphs of the average blood oxygen level–dependent (BOLD) signal intensity increase (ΔSI) including SD for left anterior descending (LAD), circumflex artery (CX), and right coronary artery (RCA). BOLD ΔSI was significantly reduced in all coronary perfusion segments supplied by an artery with fractional flow reserve (FFR) ≤0.8 (P<0.0001 for LAD, CX, and RCA). Results Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 Six patients had to be excluded from the analysis: in 3 patients CMR imaging study was prematurely stopped due to claustrophobia and 3 patients declined to undergo FFR measurement after the first CMR study with adenosine. Thirty-six patients underwent CMR study and FFR measurement and represent the study population. Baseline clinical and CMR imaging data are given in Table 1. In all patients FFR was measured in LAD, CX, and RCA. CMR and FFR Results In 17 (47.2%) patients, an FFR≤0.8 could be measured in 28 coronary arteries (25.9%). An FFR≤0.8 was detected in 9 (25%) LAD, 10 (27.8%) CX, and 8 (22.2%) RCA coronaries. Hemodynamic data during rest and adenosine for CMR and FFR examination are shown in Table 2. Table 3 provides comparison of clinical and CMR data in patients with FFR≤0.8 and >0.8. Twelve (2.1%) BOLD segments had to be excluded from analysis because of insufficient image quality during adenosine in 10 and rest in 2 segments. The D’Agostino-Pearson test for normal distribution of BOLD values yielded P=0.3567 (accept normality). Comparison of BOLD and FFR measurements yielded a correlation coefficient r=0.66 (P<0.0001) for LAD, r=0.81 (P<0.0001) for CX, and r=0.73 (P<0.0001) for RCA. BOLD signal intensity increase was significantly lower in all perfusion territories supplied by coronary arteries with FFR≤0.8 in comparison with FFR>0.8 (1.1±0.2% Table 1. Baseline Clinical and CMR Imaging Data Age, y 63.1±9.9 Men, N (%) 27 (75) Cardiovascular risk factors, N (%) Hypertension 28 (77.8) Hypercholesterolemia 19 (52.8) History of smoking 17 (47.2) Diabetes mellitus 5 (13.9) Family history for coronary artery disease 16 (44.4) CMR imaging Left ventricular end-diastolic volume index, mL/m2 72.8±17.8 Left ventricular end-systolic volume index, mL/m2 27.1±14.9 Left ventricular ejection fraction, % 64.5±10.0 CMR indicatescardiac magnetic resonance imaging. versus 1.5±0.2%; P<0.0001). This applied for the LAD (1.1±0.3% versus 1.5±0.2%; P<0.0001), CX (1.0±0.3% versus 1.5±0.2%; P<0.0001), and RCA (0.9±0.2% versus 1.5±0.2%; P<0.0001) territories. Box and whisker graphs according to the coronary perfusion territories are provided in Figure 2. ROC curve analysis yielded a BOLD cutoff value of 1.3% providing best values for sensitivity and specificity of 88.2% and 89.5%, respectively (95% CI, 76.7–97.9) on a per-patient analysis. ROC curve is provided in Figure 3. Sensitivity and specificity of the BOLD approach were 88.9% and 92.6% for LAD (95% CI, 71.1–95.6), 90.0% and 88.5% for CX (95% CI, 80.7–99.0), and 100% and 89.3% for RCA (95% CI, 86.6–99.4) perfused myocardial segments. ROC curves including area under the curve for the per-vessel analysis are provided in Figure 4. Using the cutoff value of 1.3% assessed by ROC analysis, Figure 5 provides an example of a falsepositive BOLD result in a patient with hypertensive smallvessel disease and a false-negative example in a patient with a short RCA stenosis and a resulting FFR of 0.78. Intraclass correlation coefficient yielded 0.84 for interobserver and 0.87 for intraobserver variability. Discussion We compared a T2-prepared SSFP BOLD sensitive CMR approach to FFR in patients with suspected CAD and could show that the relative BOLD signal intensity difference at rest and during adenosine highly correlated to invasively measured FFR in the corresponding supplying coronary artery. Myocardial oxygenation assessed by T2-prepared CMR imaging has Table 2. Hemodynamic Data for CMR and FFR During Rest and Adenosine Rest Adenosine Systolic blood pressure, mm Hg 142±23 132±32* Diastolic blood pressure, mm Hg 75±14 74±14 Heart rate, bpm 65±12 83±17** CMR FFR Systolic blood pressure, mm Hg 138±22 131±26* Diastolic blood pressure, mm Hg 74±14 73±13 Heart rate, bpm 62±11 77±16** CMR indicates cardiac magnetic resonance imaging; FFR, fractional flow reserve. *P<0.01. **P<0.0001. Walcher et al BOLD MRI Compared With FFR 583 Table 3. Clinical and CMR Comparison of FFR≤0.8 vs FFR>0.8 FFR≤0.8 (N=17) FFR>0.8 (N=19) P χ2 Age, y 64.5±8.2 61.9±11.3 0.4517 0.4 Men, N (%) 12 (70.6) 15 (78.9) 0.7060 6.6 Cardiovascular risk factors, N (%) Hypertension 13 (76.5) 15 (78.9) 0.9999 0.1 Hypercholesterolemia 7 (41.2) 12 (63.2) 0.3161 0.5 History of smoking 5 (29.4) 12 (63.2) 0.0543 0.5 Diabetes mellitus 3 (17.6) 2 (10.5) 0.6504 6.0 Family history for coronary artery disease 8 (47.1) 8 (42.1) 0.9999 0.2 68.1±18.0 77.5±16.8 0.1285 1.6 Left ventricular end-systolic volume index, mL/m 26.0±17.1 28.1±12.8 0.6815 0.5 Left ventricular ejection fraction, % 64.1±11.8 65.0±8.1 0.7961 <0.01 CMR imaging Left ventricular end-diastolic volume index, mL/m2 2 Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 CMR indicates cardiac magnetic resonance imaging; FFR, fractional flow reserve. previously been shown to be able to estimate oxygen saturation and to be exponentially related to vasodilator-induced increases of blood flow.9,21 Therefore, this technique appears to be able to assess myocardial ischemia. A previously described BOLD sensitive CMR approach11 was evaluated for the detection of inducible myocardial ischemia. We now demonstrate that BOLD analysis is suitable to detect hemodynamic significant coronary lesions determined by an FFR≤0.8. In the myocardial segments supplied by the coronary arteries with an FFR≤0.8 BOLD signal intensity increase was significantly lower than in those segments perfused by a coronary artery with an FFR>0.8. This correlation was demonstrated for all coronary arteries but also for each separate perfusion territory for the LAD, CX, and RCA. ROC analyses yielded good sensitivity and specificity of the BOLD analysis for detection of significant coronary lesion. A recently published manuscript showed dissociation between BOLD sensitive CMR and positron emission tomography indicating differences between ischemia and myocardial oxygenation.22 However, the latter study compared a single midventricular BOLD sensitive CMR slice to a positron emission tomographic 3-dimensional imaging approach covering the entire myocardium. Figure 3. Receiver-operating characteristics curve of blood oxygen level–dependent cardiac magnetic resonance imaging for the diagnostic accuracy to detect a patient with a fractional flow reserve ≤0.8 yielded a sensitivity of 88.2% and specificity of 89.5%. Moreover, BOLD imaging was acquired after 90 seconds, whereas positron emission tomography after 7 minutes of adenosine infusion at the same rate. Therefore, the results and conclusions of that article may be misleading and cannot be applied to our study. Diagnostic accuracies provided by BOLD CMR in the detection of significant coronary artery stenosis seem to be similar to those found by first-pass perfusion CMR using FFR as a gold standard.23 We have previously shown that BOLD imaging correlates to ischemia detected by CMR perfusion imaging.11 However, perfusion analysis was evaluated visually in that study and was compared with quantitative BOLD analysis. A semiquantitative analysis including MPR calculation seems to be more adequate for comparison of MPR and relative BOLD signal intensity increase during adenosine. This has been recently evaluated by Jahnke et al8 in 50 patients yielding similar good sensitivities and specificities for detection of coronary stenoses with a diameter reduction ≥50%. Hence, the BOLD sensitive CMR approach, which visualizes changes in myocardial oxygenation, appears capable for detection of relevant CAD. However, comparing this functional approach with an anatomical evaluation of the degree of coronary luminal narrowing by quantitative coronary angiography serving as the reference standard seems inappropriate. Rather, it should be compared with the physiological assessment of coronary artery stenoses by invasive measurement of the FFR. Thus, the diagnostic accuracy of BOLD imaging was compared with FFR. Detection of inducible myocardial ischemia is a main clinical indication for CMR. Because BOLD imaging relies on detection of different oxygenation in myocardial tissue that serves as an endogenous contrast, it does not require the application of exogenous contrast agents as surrogates for evaluation of myocardial perfusion. Because of its independency to accurate timing of contrast bolus arrival and first pass, spatial resolution can be improved. Furthermore, a 3-dimensional approach, as recently demonstrated,8 could be implemented for complete coverage of the entire 584 Circ Cardiovasc Imaging September 2012 Figure 4. Receiver-operating characteristics curves on a per-vessel basis showing the diagnostic accuracy of blood oxygen level–dependent cardiac magnetic resonance imaging in left anterior descending (LAD), circumflex artery (CX), and right coronary artery (RCA). Area under the curve (AUC) including 95% CI and P values are provided. Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 myocardium. The use of exogenous contrast agents could possibly induce nephrogenic systemic fibrosis,24 which could be avoided by the use of an imaging technique without the need of contrast agents representing another potential benefit of BOLD imaging. Because BOLD CMR yields similar diagnostic accuracies compared with contrast–enhanced perfusion CMR, it represents a potential alternative, especially, in patients with significant renal dysfunction. Limitations The investigated patient population was relatively small. Hence, cutoff values and diagnostic accuracy could alter in a larger cohort. However, BOLD imaging and FFR measurements in all 3 coronary arteries during adenosine infusion were performed in all patients and showed good diagnostic accuracies. Another possible limitation of our study is the fact that we did not perform signal intensity correction for heart rate. We included a selected patient population with stable angina and previous pathological or inconclusive stress test. To what extend our results could be postulated for a larger unselected patient cohort remains unclear. Further, larger studies are warranted to show the potential prognostic value of BOLD CMR. The BOLD effect is partly dependent on the blood flow. These effects might have influenced our data, because we have not monitored coronary blood flow during adenosine and rest, and could present a potential limitation for the presented study. Although drug-induced vasodilation is associated with a dose-dependent increase in blood flow,9 it is difficult to differentiate to what extent the observed BOLD effect is because of blood flow. An example of a false-positive CMR result possibly because of impaired coronary blood flow in a patient with small-vessel disease is presented in Figure 5. Because we did not include late gadolinium enhancement imaging in our study, we cannot conclude about its potential incremental value. Conclusions BOLD CMR offers an alternative to contrast–enhanced firstpass perfusion for the detection of hemodynamic significant CAD. Figure 5. An example of a false-positive cardiac magnetic resonance imaging (CMR) with pathological blood oxygen level–dependent (BOLD) signal intensity increase in the left anterior descending (LAD) territory without corresponding stenosis in the LAD (fractional flow reserve [FFR] 0.87). Walcher et al BOLD MRI Compared With FFR 585 Figure 6. Right coronary artery (RCA) stenosis with reduced fractional flow reserve (FFR) (0.80) in a patient without reduced blood oxygen level– dependent (BOLD) signal intensity increase in the RCA perfused segments as an example for a false-negative cardiac magnetic resonance imaging (CMR) result. Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 Sources of Funding This study was, in part, supported by a grant of the University of Ulm (L.SBN.0050). None. Disclosures References 1. Schwitter J, Nanz D, Kneifel S, Bertschinger K, Büchi M, Knüsel PR, Marincek B, Lüscher TF, von Schulthess GK. 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Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 CLINICAL PERSPECTIVE T2-prepared steady-state free precession blood oxygen level–dependent cardiac magnetic resonance imaging is based on different magnetic properties of oxyhemoglobin and deoxyhemoglobin. This results in a relative decrease of T2* and T2 relaxation time in ischemic and thus lower oxygenated myocardium. In our study, we demonstrate that this effect correlates to invasively measured fractional flow reserve in the respective coronary artery. Our described approach warrants consideration as an alternative to contrast–enhanced perfusion studies, especially in patients with severe renal failure in which the use of exogenous contrast agents should be avoided. Myocardial Perfusion Reserve Assessed by T2-Prepared Steady-State Free Precession Blood Oxygen Level−Dependent Magnetic Resonance Imaging in Comparison to Fractional Flow Reserve Thomas Walcher, Robert Manzke, Vinzenz Hombach, Wolfgang Rottbauer, Jochen Wöhrle and Peter Bernhardt Downloaded from http://circimaging.ahajournals.org/ by guest on May 7, 2017 Circ Cardiovasc Imaging. 2012;5:580-586; originally published online August 1, 2012; doi: 10.1161/CIRCIMAGING.111.971507 Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2012 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-9651. 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