Author + information
- Received October 18, 2005
- Revision received January 5, 2006
- Accepted January 9, 2006
- Published online June 6, 2006.
- Habib Samady, MD, FACC⁎,⁎ (, )
- Wolfgang Lepper, MD†,
- Eric R. Powers, MD, FACC‡,
- Kevin Wei, MD, FACC∥,1,
- Michael Ragosta, MD, FACC⁎,
- Gregory G. Bishop, MD‡,
- Ian J. Sarembock, MD, FACC‡,
- Lawrence Gimple, MD, FACC‡,
- Denny D. Watson, PhD§,
- George A. Beller, MD, MACC‡ and
- Kurt G. Barringhaus, MD¶
- ↵⁎Reprint requests and correspondence:
Dr. Habib Samady, Andreas Gruentzig Cardiovascular Center, Emory University School of Medicine, 1364 Clifton Road NE, Atlanta, Georgia 30322.
Objectives We hypothesized that fractional flow reserve (FFR) of an infarct-related artery (IRA) early after myocardial infarction (MI) identifies inducible ischemia on noninvasive imaging.
Background Early after MI, IRAs frequently have angiographically indeterminant lesions. Whether FFR can detect reversible perfusion defects early after MI when dynamic microvascular abnormalities are present is not known.
Methods Rest and dipyridamole (DP)-stress 99mTc sestamibi single-photon emission computed tomography (SPECT) were performed in 48 patients 3.7 ± 1.3 days after MI, with 23 patients undergoing concurrent myocardial contrast echocardiography (MCE). Angiography, FFR, and percutaneous coronary intervention (PCI) of the IRA (as necessary) were subsequently performed. Follow-up SPECT was performed 11 weeks after PCI to identify true reversibility on baseline SPECT.
Results The sensitivity, specificity, positive and negative predictive value, and concordance of FFR ≤0.75 for detecting reversibility on SPECT were 88%, 50%, 68%, 89%, and 71% (chi-square <0.001), respectively; which improved to 88%, 93%, 88%, 93%, and 91% (chi-square <0.001), respectively, for the detection of true reversibility. The corresponding values of FFR ≤0.75 for detecting reversibility on DP-MCE were 90%, 100%, 100%, 75%, and 93% (chi-square <0.001), respectively, and on either SPECT or MCE were 88%, 93%, 91%, 91%, and 91% (chi-square <0.001), respectively. The optimal FFR value for discriminating inducible ischemia on noninvasive imaging was 0.78.
Conclusions Fractional flow reserve of the IRA accurately identifies reversibility on noninvasive imaging early after MI. These findings support the utility of FFR early after MI.
Risk stratification after myocardial infarction (MI) may be performed either noninvasively (1–3) or angiographically (4,5). The latter provides only anatomic information, and stenoses of the infarct-related artery (IRA) often appear indeterminate.
Fractional flow reserve (FFR) has been developed as an invasive physiologic index of lesion severity and, if validated in this setting, would allow combined anatomic and physiologic evaluation of IRAs to determine suitability for revascularization. Although a FFR ≤0.75 correlates well with noninvasive determinants of ischemia in normal myocardium and late after MI (6,7), it is not known whether FFR has utility early after MI, a period characterized by microvascular injury and increases in microvascular resistance as well as dynamic flow changes.
We hypothesized that a FFR ≤0.75 of the IRA early after stabilized MI will correlate with inducible ischemia on noninvasive imaging. Although dipyridamole (DP)-stress 99mTc-sestamibi single-photon emission computed tomography (SPECT) is frequently used for early post-infarction risk stratification, it may underestimate reversibility early after MI. We therefore also compared FFR to DP myocardial contrast echocardiography (MCE), which offers better spatial resolution than SPECT.
The Human Investigation Committee at the University of Virginia approved the protocol, and all patients consented to participate in the study. Patients referred for angiography two days after non–ST-segment elevation myocardial infarction (STEMI) and three days after STEMI were enrolled. The diagnosis of MI was supported by typical ischemic chest pain and/or a troponin I (TnI) ≥5 with electrocardiographic changes of ischemia. Exclusion criteria were: 1) prior MI within the infarction bed; 2) ongoing ischemia or hemodynamic instability; 3) prior bypass of the index artery; 4) contraindication to DP or FFR; 5) complex three-vessel or left main disease; or 6) occlusion of or inability to determine the IRA lesion.
Catheterization and angiography
Biplane left ventriculography was performed in right and left anterior oblique views. The infarct risk area was identified by two blinded investigators and defined as the number of segments on ventriculography supplied by the culprit lesion divided by a total of 14 segments (corresponding to the SPECT program).
A single observer performed quantitative coronary angiography (QCA) offline using a computer-assisted program (DICOM, Heartlab Inc., Westerly, Rhode Island) as previously described (8). The luminal diameter proximal and distal to the stenosis (reference diameter) and minimal luminal diameter were determined for all lesions. The percent diameter stenosis (DS) was calculated as the ratio of the minimal luminal diameter to reference diameter.
Determination of FFR
Following angiography, FFR was determined using a 0.014-inch sensor-tipped high-fidelity pressure wire (RADI Medical, Uppsala, Sweden) as previously described (8). Heparin (50 U/kg) was administered intravenously. Simultaneous distal coronary and aortic pressures were recorded at baseline and during hyperemia (induced by intracoronary adenosine-30 μg in the right coronary artery and 40 to 60 μg in the left coronary artery). The FFR was calculated as the ratio of the mean distal intracoronary pressure to mean aortic pressure at the time of peak hyperemia. The FFR measurements were repeated after percutaneous coronary intervention (PCI) in 37 of 43 patients.
Percutaneous coronary intervention was performed at the discretion of the clinician and interventionalist. All patients received glycoprotein IIb/IIIa inhibitors and intracoronary stents.
Rest-DP stress 99mTc-sestamibi SPECT and MCE were performed concurrently within 24 h of angiography and FFR determination. One hour after injection of 240 to 300 MBq of 99mTc-sestamibi at rest, SPECT imaging was performed using a Picker Prism 3000 triple-headed gamma camera (Picker, Cleveland, Ohio), followed by resting MCE. Three hours later, 0.56 mg · kg−1of dipyridamole was administered over 4 min, followed by an intravenous injection of 750 to 900 MBq of 99mTc-sestamibi. Immediately following the administration of 99mTc-sestamibi, MCE was repeated. One hour later, stress SPECT images were obtained. Continuous monitoring of the electrocardiogram and vital signs were obtained during stress. Repeat rest-DP SPECT studies were performed three months following PCI.
Quantitative determination of segmental 99mTc-sestamibi uptake was performed using the University of Virginia program (14 segments per patient) (9). Two observers interpreted SPECT studies. Discordant interpretations were resolved by consensus. Individual segments were classified as being normal or abnormal. Abnormal stress perfusion defects were further classified as mild or severe. The abnormal stress images were compared with corresponding rest images and considered reversible, partially reversible, or fixed based on improved tracer uptake at rest. The SPECT reversibility was defined as at least one reversible or partially reversible segment in the infarct risk area.
For semiquantitative analysis, a segmental stress score (SSS) was derived from the stress images by allocating normal segments a score of 0, mild defect a score of 2, and severe defects a score of 4. Segmental rest scores (SRS) were allocated as follows: fixed defects: SRS = SSS; normal rest perfusion: SRS = 0; partially reversible mild/moderate defects: SRS = 1; partially reversible severe defects: SRS = 2. Segmental difference score (SDS), a semiquantitative marker of reversibility, was defined as the numeric difference between the stress and rest scores.
True negative SPECT was defined as a normal or fixed defect when the initial stress images were paired with post-PCI rest images (in order to adjust for known early post-MI reduced rest tracer uptake rendering reversible defects fixed). True positive SPECT was defined as reversible SPECT images (utilizing post-PCI rest images) that became fixed or normal after revascularization.
To investigate the ability of FFR to detect noninvasive ischemia in different degrees on infarction, we divided 21 patients with true noninvasive ischemia on SPECT or MCE into three groups based on TnI level: TnI <10 ng/dl, small MI; TnI 10 to 100 ng/dl, moderate MI; TnI >100 ng/dl, large MI.
For MCE, Definity (Bristol-Myers Squibb Medical Imaging, Billerica, Massachusetts) was diluted in saline and infused (AS50, Baxter, Deerfield, Illinois) at 90 to 120 mlh−1. Digital cine loops of regional function and myocardial perfusion were acquired from the apical four-, two- and three-chamber views using harmonic imaging and intermittent ultraharmonic imaging, respectively (Sonos 5500, Philips Ultrasound, Andover, Massachusetts). Ultrasound transmission was gated to end-systole. Imaging settings were held constant throughout the study. Contrast-enhanced images were obtained at pulsing intervals (PIs) of 300 ms to 8 s and acquired on a magneto-optical disk.
Rest and DP-stress studies were analyzed offline using side-by-side display by a single blinded observer. In the infarct bed (akinetic segments), normal resting flow was defined as complete myocardial opacification at a PI of <4 s (10). Perfusion defects at long pulsing intervals represented the no-reflow zone. Abnormal hyperemic flow was defined as incomplete myocardial opacification at a PI >1 to 2 s during stress. Myocardial contrast echocardiography perfusion was classified as normal if both resting and hyperemic flow were normal. Stress perfusion defects were classified as reversible or fixed using the same 14-segment model as SPECT.
Results are reported as mean ± SD unless otherwise indicated. Chi-square analysis was performed for comparison of binary variables. Comparisons between continuous variables were performed by Student ttests. A Pearson’s correlation was used to define a continuous relation between FFR and SPECT segmental difference score. The sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of FFR ≤0.75 for determining reversibility by SPECT and MCE were determined. The k statistic was used to investigate the concordance between FFR values and SPECT/MCE. Receiver-operator characteristics were calculated for FFR predicting reversibility by noninvasive testing. A p value <0.05 was considered significant.
Of 75 patients enrolled, 27 were excluded because of coronary anatomy requiring surgery, IRA occlusion, or inability to identify the IRA. The remaining 48 patients underwent baseline SPECT and FFR measurements and constituted the first FFR/SPECT analysis. Of these 48 patients, 43 underwent PCI and 37 post-PCI FFR. Five of 48 patients had fixed defects, non-critical coronary stenoses by QCA, and FFR >0.75 and were treated medically.
Follow-up SPECT was performed in 31 patients at a mean of 11 ± 9 weeks after PCI. Of these 31 patients, 24 had true positive and true negative SPECT. Post-PCI FFR was available in 21 of these patients. The second FFR/SPECT comparison consisted of 45 paired studies of baseline FFR with true positive/true negative SPECT or post-PCI FFR paired with delayed SPECT. In 23 patients who underwent MCE, baseline FFR was compared to MCE. Finally, because of lack of a perfect noninvasive gold standard, 55 FFR data points were compared to a combined noninvasive standard, defined positive if either MCE or true positive/true negative SPECT was reversible and negative if both tests were fixed. These 55 FFR data points consisted of 45 true positive/negative SPECT data (13 of which also had MCE data) and 10 patients with MCE without true positive/negative SPECT data.
Table 1shows the clinical characteristics of the 48 study patients. Seventy-three percent had STEMI and received thrombolytics. Peak TnI was 108 ± 120 ng/dl, and time from MI to catheterization was 3.7 ± 1.3 days. The MI risk area was 35 ± 13% of the myocardium. Mean DS of IRA was 75 ± 13%. Thirty-three percent had moderate (DS = 40% to 70%) lesions and 67% had DS ≥70%. Mean FFR was 0.65 ± 0.17. Post-PCI DS and FFR were 5.0 ± 7.6% and 0.94 ± 0.05, respectively.
Correlation between FFR and SPECT
Baseline SPECT was reversible in 54% of patients and fixed in 46%. Patients with reversible and fixed SPECT defects had similar infarct risk area (36 ± 13% vs. 34 ± 14%; p = NS), SSS (8.7 ± 5.0 vs. 7.5 ± 6.7; p = NS), and DS (76 ± 10 vs. 70 ± 13; p = NS). Segmental difference score was significantly higher (4.4 ± 3.0 vs. 0.1 ± 0.4, p < 0.001) and FFR significantly lower (0.58 ± 0.13 vs. 0.75 ± 0.17; p < 0.001) in patients with reversible compared with fixed SPECT. A significant inverse correlation was observed between FFR and SDS, (y = −6.9885x + 7.0233, r = −0.39, p < 0.01).
An FFR ≤0.75 had a sensitivity of 88%, specificity of 50%, positive predictive value (PPV) of 68%, negative predictive value (NPV) of 79%, and concordance of 71% for predicting the presence of a reversible defect on SPECT.
Discordances between FFR and baseline SPECT were demonstrated in 14 patients. Among 3 of 14 patients with reversible SPECT and FFR >0.75, 1 had FFR 0.83 and DS 71%, underwent PCI, and follow-up SPECT remained reversible, suggesting that baseline SPECT was false positive. The second patient had FFR 0.78 and DS 77%, underwent PCI, and follow-up SPECT normalized, suggesting true positive baseline SPECT. The third patient had FFR 0.86, DS 53% with an ulcerated lesion, underwent PCI, with follow-up SPECT becoming fixed, suggesting true positive baseline SPECT.
Follow-up SPECT was performed in 8 of 11 patients with FFR ≤0.75 and fixed SPECT defects. Six of these eight patients were reclassified as reversible when stress SPECT was paired against delayed-rest SPECT, suggesting that the baseline SPECT was falsely negative. All five MCEs available in these six patients demonstrated reversible defects (Fig. 1).
Fractional flow reserve ≤0.75 had a sensitivity of 88%, specificity of 93%, PPV of 88%, NPV of 93%, and diagnostic accuracy of 91% (chi-square <1 × 10−9) for detecting reversibility on true positive/negative SPECT (Fig. 2).
Correlation between FFR and MCE
Myocardial contrast echocardiography was reversible in 78% of patients and fixed in 22%. Fractional flow reserve in patients with reversible MCE was significantly lower than those with fixed MCE (0.58 ± 0.14 vs. 0.87 ± 0.07; p < 0.001). Fractional flow reserve ≤0.75 had a sensitivity of 90%, specificity of 100%, PPV of 100%, NPV of 75%, and a diagnostic accuracy of 93% for predicting reversible defects on MCE (chi-square <0.00005) (Fig. 3).
FFR and reversibility on SPECT or MCE
Concordance between FFR and noninvasive tests was seen in 50 of 55 patients, kappa = 91%, chi-square = 2 × 10−9(Fig. 4).A FFR ≤0.75 has a sensitivity of 88%, specificity of 94%, PPV of 91%, and NPV of 91% for predicting reversibility by combined noninvasive testing. Receiver-operator characteristic analysis identified an FFR ≤0.78 as the optimal value for detecting noninvasive reversibility (Fig. 5).
We found no significant difference in sensitivity of FFR ≤0.78 to detect true reversibility on SPECT or MCE in small, medium, and large infarct sizes (100% vs. 100% vs. 87%, respectively, p = NS).
QCA and noninvasive imaging
There was no significant difference in QCA in patients with reversible or fixed SPECT (76 ± 10% vs. 71 ± 13% p = NS), true reversible or fixed SPECT (75 ± 11% vs. 71 ± 12% p = NS), or reversible or fixed MCE (76 ± 1 2% vs. 68 ± 19%; p = NS).
Our study demonstrates that in medically stabilized patients after MI with patent IRAs, FFR ≤0.75 has: 1) high sensitivity (88%), limited specificity (50%), and a 71% diagnostic accuracy for detecting reversibility on SPECT imaging, which improves to 88%, 93%, and 92%, respectively, when only true positive SPECT studies were considered; 2) high sensitivity (89%), specificity (100%), and diagnostic accuracy (91%) for detecting reversibility on MCE; and 3) high sensitivity (91%), specificity (93%), and diagnostic accuracy (92%) for detecting reversibility using a combined SPECT/MCE gold standard. An FFR ≤0.78 was found to provide optimal discriminatory power for detecting reversibility on SPECT or MCE, with no significant loss in sensitivity to detect ischemia in large infarct sizes.
Debate has arisen regarding the accuracy of FFR after MI, as FFR determination depends upon the assumption that vasodilator-mediated hyperemia achieves a state of minimal and constant coronary resistance (8,11,12). DeBruyne et al. (7) showed that FFR identified inducible ischemia on SPECT in patients 20 ± 27 days (range 6 to 570 days) after MI, specifically excluding patients with MIs within six days of FFR assessment. Therefore, to date, whether FFR assessment of an IRA earlyafter infarction has diagnostic value has remained uncertain. In this setting, microvascular stunning and injury, thromboemboli, platelet plugging, coronary vasospasm, and endothelial dysfunction may diminish microvascular reactivity, necessary for both invasive and noninvasive physiologic testing. Several investigators have shown that myocardial flow reserve is reduced early following infarction and improves over time (13,14). Thus, the fidelity of all vasodilator-dependent physiologic studies may be affected early after MI, a time when many patients undergo risk stratification. However, we found approximately one-third of our patients to have angiographically indeterminate lesions early after MI, and we have previously shown that visual angiographic analysis frequently overestimates the hemodynamic significance of indeterminate lesions (15). Therefore, the finding that FFR correlates well with state-of-the-art noninvasive imaging suggests that it may be an acceptable alternative to noninvasive physiologic testing to evaluate moderate lesions early after MI.
We found a better correlation between FFR and MCE than between FFR and baseline SPECT in patients early after MI. This likely relates to underestimation of reversibility by SPECT imaging performed early after MI owing to falsely diminished rest tracer uptake in this time period (16–18). Our observation that the specificity of FFR ≤0.75 for detecting reversibility on SPECT increased from 50% to 93% when only true positive and negative SPECT studies were considered supports the notion. The mechanism for the underestimation of rest flow by tracer uptake early after MI is not known but may relate to the limited spatial resolution of SPECT (15 mm for SPECT vs. <1 mm for MCE) or the partial volume effect (19). Another reason for the better correlation between FFR and MCE is that these techniques both assess blood flow within the infarct bed, unlike SPECT, which provides an assessment of relative differences in blood flow between different vascular territories.
Not all patients underwent baseline MCE and post-revascularization SPECT imaging. However, no significant differences in baseline characteristics, infarct location, or DS of IRA were noted between patients who underwent the full study protocol compared with those who did not.
Given reduction in early post-MI vasodilator reserve, it is possible that both FFR and noninvasive testing underestimate the hemodynamic significance of residual lesions in IRAs.
Patients with occluded IRAs and massive infarcts with hemodynamic instability were excluded from this study; therefore, the observed relationship between FFR and residual ischemia in the IRA does not apply to that subgroup of patients. However, ability of FFR to identify noninvasive ischemia should apply to most reperfused STEMI and non-STEMI, as we enrolled consecutive unselected patients in our study.
Fractional flow reserve of the IRA accurately identifies reversibility on noninvasive imaging early after MI. These findings support the utility of FFR early after MI.
The microbubble contrast agent was provided by Bristol-Myers Squibb Medical Imaging (North Billerica, Massachusetts), and the ultrasound equipment was provided by Philips Ultrasound (Andover, Massachusetts).
↵1 Dr. Wei was the recipient of a Mentored Clinical Scientist Development Award (K08-HL03909) from the National Institutes of Health.
This study was partially supported by research grants from Radi Medical Systems (Uppsala, Sweden) and Guidant Corporation (Indianapolis, Indiana).
- Abbreviations and Acronyms
- diameter stenosis
- fractional flow reserve
- infarct-related artery
- myocardial contrast echocardiography
- myocardial infarction
- negative predictive value
- not specified
- percutaneous coronary intervention
- pulsing intervals
- positive predictive value
- quantitative coronary angiography
- segmental difference score
- single-photon emission computed tomography
- segmental rest score
- segmental stress score
- ST-segment elevation myocardial infarction
- troponin I
- Received October 18, 2005.
- Revision received January 5, 2006.
- Accepted January 9, 2006.
- American College of Cardiology Foundation
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