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Imaging Highlights of the American Heart Association 2007 Scientifıc Sessions
JACC: CARDIOVASCULAR IMAGING
VOL. 1, NO. 2, 2008
© 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/08/$34.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2008.01.012
IMAGING EXCERPTS FROM SCIENTIFIC MEETINGS
Imaging Highlights of the American Heart Association 2007 Scientific Sessions James K. Min, MD, FACC,* Leo Hofstra, MD,† Swaminatha V. Gurudevan, MD,‡ Manuel D. Cerqueira, MD, FACC, FAHA, FASNC§ New York, New York; Maastricht, the Netherlands; Irvine, California; and Cleveland, Ohio
Of the 3,780 abstracts accepted for presentation at the American Heart Association (AHA) Scientific Sessions 2007 in Orlando, 206 belonged to the cardiovascular imaging category. The following abstracts can be considered the imaging highlights of 2007. From session to session and hall to hall in our quest to get the best possible abstracts to you, a clear emphasis was placed this year on computed tomographic angiography of the coronary arteries and on multimodality imaging of atherosclerotic plaques. These techniques place give us hope for a preventive rather than reactive approach and, if well characterized in the ensuing years, they should prove worthy for better characterization of coronary vessel walls in individuals at risk. Seeking COURAGE From the Wizard of Oz. . .
Considerable controversy exists regarding the lack of added benefit reported for percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) when compared with OMT alone within the COURAGE (Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation) trial (1). This randomized controlled trial enrolled 2,287 patients who were followed for 4.6 years, with no differences identified by treatment strategy for the primary end point of death or acute myocardial infarction (1). Although one can argue the limitations of any randomized trial (2), the results of the
From the *Weill Medical College of Cornell University, New York, New York; †Academic University of Maastricht, Maastricht, the Netherlands; ‡University of California Irvine School of Medicine, Irvine; and the §Cleveland Clinic Foundation, Cleveland, Ohio. Dr. Min is on the Speakers’ Bureau of and is a consultant for GE Healthcare. Manuscript received 23 January 2008; accepted January 30, 2008.
COURAGE trial suggested to us that, in chronic, stable angina patients, PCI may be initially safely deferred. Nearly a decade ago, when planning the COURAGE trial, the executive committee had decided to include several substudies that included evaluation of the role of ischemia with the use of quantitative myocardial perfusion single-photon emission computed tomography (SPECT) imaging (MPI-SPECT) (3). These substudies included evaluating prognosis in relation to pre-treatment MPI assessment, utility of MPI to discriminate optimal treatment strategies for patients with recurrent angina, and the role of sequential ischemia testing by MPI (3). The MPI substudy of the COURAGE trial was reported at the late breaking clinical trials and included serial MPI evaluation in 314 of the 2,287 patients (4). Serial MPI in patients included a pre-treatment and 18-month follow-up MPI study to examine the impact of intercurrent treatment on myocardial ischemia. Although there was no definitive rationale for the timing of the follow-up scan, numerous key opinion leaders in the field of cardiovascular medicine agreed by expert consensus on this follow-up time. The opinion of the nuclear substudy leadership within COURAGE was that an 18-month window would permit sufficient time for the effects of medical therapy to be observed as well as to be beyond the window of in-stent restenosis. For entry into the MPI COURAGE substudy, patients were required to exhibit evidence of ischemia upon study entry, as determined by the local clinical investigator. A total of 25 of the 50 COURAGE sites participated in this substudy and included sites with large-volume MPI laboratories that frequently rely on perfusion imaging data to guide therapeutic decision making. The
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Ischemia Reduction ≥5%
50%
40% 33.3%
30% 19.8%
20%
p=0.004
10%
0%
PCI + OMT (n=159)
OMT (n=155)
Figure 1. Percent of Patients in the COURAGE MPI Substudy With Ischemia Reduction >5% Myocardium (n ⴝ 314) COURAGE ⫽ Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation; OMT ⫽ optimal medical therapy; PCI ⫽ percutaneous coronary intervention.
First, it reflected a selected subset of only 14% of the COURAGE-enrolled patients, and myocardial perfusion single-photon emission computed tomography (MPS) was not mandated within COURAGE, so this sample thereby reflects a limited understanding of the role of imaging in therapeutic decision-making. Second, any association of prognosis as it relates to MPI-identified ischemia and treatment strategy of angina patients cannot be established by the COURAGE MPI substudy because of a lack of power. These results, then, should be viewed as useful primarily for hypothesis-generating purposes or as helpful for devising future clinical trials. Definitive statements about the benefit of PCI ⫹ OMT over OMT alone 100%
Ischemia Reduction ≥5%
requirement that study entry be limited to those patients with ischemia was based upon American College of Cardiology (ACC)/AHA guidelines for targeting anatomic stenosis that may benefit from PCI (5). Furthermore, previous smaller series have revealed demonstrable reductions in provocative ischemia with medical therapy, as noted in a recent review (3). In one report by Schwartz et al. (6), nearly one-half of patients with chronic coronary disease exhibited a sizeable reduction in ischemia after 6 months of statin therapy. Thus, at the study’s initiation, it was unclear whether reductions in MPI-identified ischemia would be favored in either of the 2 arms. Shaw et al. (4) presented the results of this substudy, reporting a marked reduction in ischemia with PCI ⫹ OMT when compared with OMT alone. In fact, 33% of the PCI ⫹ OMT patients exhibited a reduction in ischemia that encumbered 5% or more of the myocardium based on quantitative MPI, as compared with only 20% for those enrolled in the OMT arm (p ⫽ 0.004) (Fig. 1). This threshold of a change in ischemia ⱖ5% of the myocardium was chosen because of its prognostic significance and the fact that it exceeded inter-test repeatability (4). Although an inclusion criterion limited entry of patients to those with ischemia, the COURAGE substudy patients, on average, had only mild ischemia (approximately 8% of the myocardium being ischemic) before treatment. Thus, a greater benefit was anticipated for those patients with a greater risk of ischemia (i.e., moderate-to-severe ischemia or ⱖ10% of the myocardium). In keeping with this expectation, the results from this substudy revealed that nearly 80% of patients with moderate-to-severe severe pretreatment ischemia exhibited a marked ischemia reduction of ⱖ5% of the myocardium with PCI ⫹ OMT as compared with only 52% of OMT patients (p ⫽ 0.007) (Fig. 2). Thus, it appears that this latter threshold may prove to be an effective entry criterion for future randomized trials. These latter results are consistent with the tenet in therapeutic intervention that greater-risk patients receive a greater proportional benefit with intervention (7). To that extent, future work in this area would be interesting to examine any added benefit with PCI over OMT. The COURAGE MPI substudy examined the primary end point of ischemia reduction and was underpowered to examine changes in prognosis. Readers should, therefore, adopt these results cautiously and realize the limitations of the report.
80%
(n=105) 78.0%
60%
52.0% p=0.007
40%
20%
0%
PCI + OMT (n=54)
OMT (n=51)
Figure 2. Percent of Patients in the COURAGE MPI Substudy With Ischemia Reduction >5% Myocardium Who Had Moderate-to-Severe Pre-Treatment Ischemia Abbreviations as in Figure 1.
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as they relate to long-term outcome cannot be inferred from this substudy. Third, this substudy was powered to examine an overall effect of changes in ischemia and did not consider any key patient subsets, including those with previous myocardial infarction, with diabetes, who were women, or those with impaired left ventricular function. This latter point is critical for clinicians desiring to implement this information into their daily practice. Finally, the COURAGE MPI substudy results do not endorse routine 1-year MPS studies. That is, patients who are angina-free at 1 year do not require additional, unnecessary MPS. These results when using serial MPI remain outside of standards put forth in the recent appropriateness criteria (8). Thus, we await additional guidance from updated documents from the ACC to evaluate the role of serial MPI for patients with chronic coronary disease. The COURAGE MPI substudy results are groundbreaking in that they reflect a decade-long inquiry by the COURAGE investigators to move MPI beyond the role of risk stratification into a realm of fully integrated clinical-decision making. Because reductions in ischemia were associated with improvements in angina, the COURAGE MPI substudy now establishes the heretofore-unmet standard of effectiveness in cardiovascular imaging, namely, the demonstration of improved health benefits in patients undergoing MPI-guided therapy. Additional clinical trials are still necessary to elicit the role of cardiac imaging for guidance of therapeutic decision making in other areas of cardiovascular medicine. To date, cardiac imaging trials have been generally poorly funded, and the lion’s share of evidence has been derived from prospective, observational registries. If any single take-home lesson was learned by the COURAGE substudy, it is that imaging can be an important, if not critical, component of a clinical trial. Trialists embarking on future controlled clinical studies can now consider the benefit of cardiovascular imaging in the context of not only future risk stratification, but also of improving health outcomes, especially as it relates to its use as an intermediate outcome. Along the line of myocardial ischemia assessment, the results of a multicenter Phase III trial that used contrast echocardiography with a synthetic biodegradable ultrasound contrast material, perflubutane polymer microspheres (Imagify, Acusphere, Watertown, Massachusetts), were also presented at the AHA 2007 Scientific Sessions (9).
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Presented by Roxy Senior, on behalf of investigators of RAMP (the Real-time Assessment of Myocardial Perfusion Imaging)-1 (n ⫽ 285) and RAMP-2 (n ⫽ 377 patients) phase III trials, these studies took place at 28 international centers in 662 patients presenting with angina. The primary analyses focused on the safety and efficacy of the perflubutane polymer microspheres. These data were compared with quantitative myocardial perfusion studies performed with 99mTc-labeled perfusion tracers imaging at rest and after dipyridamole stress. All images were inspected for the presence of wall motion abnormalities and/or perfusion defects by independent blinded readers, with diagnostic accuracy of perflubutane polymer microsphere ischemia detection determined by quantitative coronary angiography in a non-inferiority and superiority analysis. In the RAMP-1 and -2 studies, the prevalence of significant coronary artery disease was 44% and 58% of patients, respectively. The contrast echocardiography results were demonstrated to be either noninferior or superior to nuclear imaging for accuracy, sensitivity, and specificity. Except for a lone case of hypersensitivity in one study patient, no side effects of the new contrast agent were observed. In this issue of JACC: Cardiovascular Imaging, the results of OPTIMIZE trial highlighting the role of ultrasound contrast for stress testing also are presented. Readers are, however, cautioned that the use of contrast in the stress setting is not an approved indication and is considered off-label. Particular care should be given to the use of contrast echocardiography, given the recent black box warning for the use of ultrasound contrast agents (10). Similarly, Carrascosa et al. (11) studied 47 patients who underwent both stress/rest 99mTc sestamibi SPECT and rest-dipyridamole stress multidetector computed tomography (MDCT) cardiac scans. Overall sensitivity and specificity to detect stress-induced ischemia as defined by reduction in myocardial contrast enhancement was 77% and 99%, respectively, compared with SPECT. Reductions of myocardial contrast enhancement on MDCT scans at rest were associated with high a sensitivity and specificity of 96% and 98%, respectively, for the detection of myocardial scar. On the other hand, Shapiro et al. (12) examined the significance of hypoattenuated left ventricular myocardium in patients after a first ST-segment elevation myocardial infarction. Using 64-slice coronary computed tomographic angiography (CCTA), 17 patients treated with primary percutaneous coronary intervention (average door-to-
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balloon time 81 ⫾ 34 min) were evaluated with both CCTA and cardiac magnetic resonance imaging (CMR; mean 2.9 ⫾ 1.0 days after ST-segment elevation myocardial infarction) and a follow-up CMR at 6 months. Of 680 myocardial segments evaluated, 204 (30%) demonstrated a hypoattenuation pattern that was defined as a perfusion defect. Transmurality of perfusion defects, as imaged by CCTA, were inversely proportional to left ventricular recovery. Improved regional left ventricular function score, when assessed with CMR, was associated with segments with ⬍25% transmurality (42 of 65, 65%) but not ⬎75% transmurality of PD (2 of 23, 9%). On the basis of these preliminary results, CCTA holds promise in our ability to assess myocardial viability and predict left ventricular recovery after successful revascularization in patients presenting with first acute ST-segment elevation myocardial infarction. In a parallel study of 52 consecutive patients presenting with first acute myocardial infarction, noncontrast 64-row CCTA was performed immediately after iodine exposure from selective coronary angiography (13). The CCTA scans were compared with electrocardiogram-gated thallium-201 SPECT scans within 5 days and 6 months after onset of myocardial infarction. Hyperattenuated areas were considered areas of myocardial delayed enhancement and transmurality and were compared with angiographic, SPECT, and clinical data at 6 months. Three groups were identified: group A demonstrated transmural delayed enhancement (DE) (n ⫽ 18) (Fig. 3), group B demonstrated subendocardial DE (n ⫽ 20), and group C demonstrated no DE (n ⫽ 14). Group A demonstrated greater peak creatine kinase, myocardial band (483 ⫾ 286 IU/ml vs. group B, 223 ⫾ 155 IU/ml and group C, 129 ⫾ 117 IU/ml, respectively, p ⫽ 0.0017) with lower incidences of myocardial blush grade 3 (22% vs, group B 67% and group C 75%, p ⫽ 0.0071) and left ventricular ejection fraction (41 ⫾ 8% vs. group B 53 ⫾ 13% and group C 62 ⫾ 11%, p ⬍ 0.001). Furthermore, during the 6-month period, left ventricular end-diastolic volume increased significantly (110 ⫾ 25 mm3 to 125 ⫾ 21 mm3, p ⫽ 0.042) in Group A, whereas rates of rehospitalization for heart failure (p ⫽ 0.0121) more often were observed. CORE-64: Inching Closer to the Core Expectation!
Coronary computed tomographic angiography continues to be evaluated as an exciting new
Figure 3. Transmural Hyperenhancement by 64-Slice Computed Tomography in Group A Adapted from Sato et al. (12).
diagnostic tool for the assessment of obstructive coronary disease. Although a large number of single-center studies have been reported, the CORE-64 (Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography using 64 Detectors) study, presented at the AHA 2007 Scientific Sessions, represented the first prospective, multicenter study to compare 64-slice CCTA to standard quantitative coronary arteriography (Fig. 4) (14). This study, undertaken in 9 centers in 7 countries, enrolled 291 patients (⬎40 years of age; calcium scores ⬍600) who first underwent CCTA followed by clinically indicated conventional coronary angiography, with a primary end point of diagnostic ability of 64-slice CCTA to identify patients with significant coronary artery disease (CAD). All nonstented segments ⬎1.5 mm were assessed by 2 independent core laboratories with 2 blinded readers per laboratory. Coronary artery stenosis ⬎50% by quantitative coronary angiography (QCA) was considered significant, and patients were followed clinically for cardiovascular events, including revascularization. Coronary artery segments were evaluable in 97% of 291 patients, and the prevalence of significant CAD by QCA was 56%. On a per-patient based analysis, quantitative analysis of stenosis by CCTA revealed an area under the curve of 0.93 (95% confidence interval [CI] 0.90 to 0.96) in
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Patients >40 yrs, suspected CAD, referred for clinical cath
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64-slice MDCTA
Cardiac Catheterization
Clinical Follow-up
0.5 mm thickness
<30 days
30 days
MDCT Angiography Calcium score
Conventional Invasive Angiography
Ca+ >600 Registry
Angiographic Core Lab
MDCT Core Lab
Figure 4. Study Design of the CORE-64 Study Ca ⫽ calcium; CAD ⫽ coronary artery disease; MDCT ⫽ multidetector computed tomography; MDCTA ⫽ multidetector computed tomographic angiography.
comparison with QCA; the overall sensitivity of quantitative CCTA for detection of a significant stenosis ⬎50% was 0.85 (95% CI 0.79 to 0.90) and specificity 0.90 (95% CI 0.83 to 0.94) (Fig. 5). Given the disease prevalence rate of 56%, the positive and negative predictive values were 0.91 and 0.83, respectively. Interestingly, on the patient level, CCTA demonstrated an equivalent ability to
1.0 0.9
ROC Area = 0.93 95% CI [0.90-0.96]
0.8 0.7
Sensitivity
256
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
1-Specificity Sensitivity
Specificity
PPV
0.85
0.90
0.91
NPV 0.83
(0.79-0.90)
(0.83-0.94)
(0.86-0.95)
(0.75-0.89)
Figure 5. ROC Curve and Diagnostic Test Performance and Characteristics of 64-Slice Coronary Computed Tomographic Angiography in the CORE-64 Study CI ⫽ confidence interval; CORE-64 ⫽ Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography using 64 Detectors; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value; ROC ⫽ receiveroperator characteristics.
identify the need for coronary revascularization, when compared with QCA. The diagnostic performance of CCTA on “per-patient basis” appeared to be better as compared to the assessment on “pervessel basis” (Fig. 6). Given the aforementioned results, the study concluded that 64 detector CCTA can be used to evaluate symptomatic patients for significant CAD as well as the potential need for revascularization procedures. This late-breaking study, supported by Toshiba Medical Systems and Bracco, was presented at the AHA 2007 by Julie Miller, MD, of Johns-Hopkins Medical Center on behalf of the CORE-64 investigators. Although this study confirmed the strong performance of CCTA imaging, particularly a strong positive predictive value, more evidence is still necessary for appropriateness of indications of CCTA in clinical practice. However, the CORE-64 study moves the field closer to the “core” goal of eventually replacing standard invasive coronary angiography by a noninvasive test as a diagnostic tool. In another interesting diagnostic accuracy study, Abdellaoui et al. (15) from the Institut Hospitalier Jacques Cartier, France, investigated the role of CCTA in the detection of coronary artery bypass graft patency. This study evaluated the graft patency rate in the early post-operative period after off-pump bypass grafts and compared the patency rates with standard on-pump procedures. Of the 134 enrolled patients (median age, 66 years), 11 were excluded because of arrhythmias or tachycardia in despite beta blockers; in 15 patients, CCTA could not be performed because of the inaccessibility of CCTA at the time of discharge. Of the remaining 108 patients, CCTA findings were compared in 188 grafts from 69 patients after on-pump surgery, with 125 grafts in 39 patients after an off-pump procedure. The overall graft patency was 98%, including 97% on-pump and 98% off-pump procedures. On the other hand, in a 5-year follow-up of 2,971 consecutive primarily low- and intermediaterisk chest pain patients, all-cause mortality was examined in relation to obstructive plaque identified with CCTA (Fig. 7) (16). Coronary artery plaque was assessed by the absence of detectable plaque, nonobstructive plaque, and obstructive plaque. Compared with adults with no evident coronary artery plaque, adults with obstructive coronary plaque were much more likely to die if 1-vessel obstructive plaque (risk ratio [RR] 5.6, 95% CI 1.56 to 18.9, p ⫽ 0.01), 2-vessel obstructive plaque (RR 6.9 95% CI 1.6 to 32.9, p ⫽ 0.03), or 3-vessel
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1.0 0.9 0.8
Sensitivity
obstructive plaque (RR 26.0, 95% CI 3.6 to 92.1, p ⫽ 0.001) was present. Importantly, even the presence of nonobstructive plaque conferred increased risk of mortality (RR 2.9, 95% CI 1.6 to 11.5, p ⫽ 0.01). In keeping with other studies, the 5-year rate of death for chest pain patients without detectable coronary artery plaque by CCTA was low (1.8%). In addition to this long-term follow-up, several investigations were presented that examined the prognostic value of CCTA to detect other end points, including major adverse cardiac events (Table 1) (17–23).
0.7
ROC Area
0.6
Patient = 0.93 [0.90-0.96] Vessel = 0.91 [0.88-0.93]
0.5 0.4 0.3 0.2 0.1 0.0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
CT Angiography Technology: Faster and Better
The 2007 Scientific Sessions examined 2 recently introduced features to MDCT, namely improved temporal resolution and increased numbers of detector rows, demonstrating the feasibility of CCTA use in individuals with higher heart rates and with less artifact, respectively. Burgstahler et al. (24) studied the diagnostic accuracy of dual-source CT (DSCT) scanners with improved 83-ms temporal resolution in 100 consecutive patients with known or suspected CAD, in which image quality using DSCT was evaluated weighing the impact of heart rate, heart rate variability and calcification. The average heart rate was 64.0 ⫾ 13.2 beats/min, mean heart rate variability 23.6 ⫾ 36.2 beats/examination, and mean coronary artery calcium score 786.5 ⫾ 965.9 Agatston units. Of 90.2% segments that were evaluable, per-patient and -segment sensitivity compared with quantitative coronary angiography, specificity, and positive and negative predictive values were 100%, 81.5%, 93.6%, and 100% and 91.1%, 92.0%, 75.4%, and 97.5%, respectively. Notably, image quality was unaffected by increasing heart rate but was impacted by heart rate variability and coronary artery calcification. Diagnostic accuracy was unrelated to either heart rate or variability, but only to coronary artery calcification. In a similar study of 65 consecutive patients with suspected CAD with an average heart rate of 68 ⫾ 9 beats/min, per-patient and per-segment accuracy compared with quantitative coronary angiography for sensitivity, specificity, and positive and negative predictive values were 100%, 83.3%, 86.9%, and 100% and 98.3%, 96.7%, 86.6%, and 99.9%, respectively (25). Notably, only 2 of 1,160 coronary artery segments were unevaluable (0.17%). In this cohort,
False Positive Rate Sensitivity
Specificity
PPV
NPV
0.85 0.76
0.90 0.93
0.91 0.82
0.83 0.89
Patient All Vessels
Figure 6. Comparison of “Per-Patient” and “Per-Vessel” Performance by 64-Slice Coronary Computed Tomographic Angiography in the CORE-64 Study Abbreviations as in Figure 5.
the average coronary artery calcium score was low (100 ⫾ 560 Agatston units), which may explain the improved specificity. Finally, Leber et al. (26) examined 130 patients with intermediate likelihood for significant coronary artery disease who were referred for DSCT and invasive coronary angiography. Compared with invasive coronary angiography, DSCT resulted in a sensitivity, specificity, and positive predictive value of 100%, 96%, and 76%, respectively. Notably, accuracy to detect a ⬎75% stenosis did not differ in
30 25 Relative Risk
20 15 10 5 0
Non-obstructive
1V
2V
3V
Figure 7. Relative Risk for All-Cause Mortality by Number of Epicardial Coronary Artery Vessels With Nonobstructive, 1-, 2-, or 3-Vessel Obstructive Plaque as Identified With Computed Tomography
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Table 1. Studies Evaluating the Prognostic Value of CCTA CCTA Predictor
Clinical End Point
Van Werkhoven et al. (17)
Author (Ref. #)
426
⬎50% obstructive plaque ⫹ abnormal MPI versus ⬍50% plaque ⫹ normal MPI
60-day cardiac death, nonfatal MI, UA, TVR
39% vs. 8%
Kunimasa et al. (18)
760
Nonobstructive low density plaques by CCTA
MI, UA, cardiac death
MI (0.94% vs. 0.05%), UA (1.13% vs. 0.64%), ACS (2.08% vs. 0.7%), cardiac death (0.37% vs. 0.23%)
0.002
Ahmadi et al. (19)
493
Obstructive plaque by CCTA
40-month follow-up of MI or death
100% event free survival for patients with no obstructive plaque; HR 16.6 (95% CI 4.9 to 55.2)
0.0001
Aggarwal et al. (20)
506
No plaque versus nonobstructive noncalcified plaque
34-month follow-up of TVR
0% versus 40%
1,017
Obstructive stenosis
602 days for all-cause death
Exclusion of stenosis with low risk of death
218 abnormal or equivocal stress test
Obstructive stenosis
8 months cardiac death, MI, TVR, UA
100% event-free survival for no plaque; HR 12.59 for obstructive stenosis
0.01
No coronary stenosis versus coronary stenosis‘
2-year cardiac death, MI, UA, TVR
100% event-free survival with no coronary stenosis
N/A
Steinbigler et al. (21)
Azevedo et al. (22)
Aldrovandi et al. (23)
No. of Patients
187
Results
p Value ⬍0.001
⬍0.05
ACS ⫽ acute coronary syndromes; CCTA ⫽ coronary computed tomographic angiography; CI ⫽ confidence interval; HR ⫽ hazard ratio; MI ⫽ myocardial infarction; MPI ⫽ myocardial perfusion single-photon emission computed tomography imaging; N/A ⫽ not applicable; TVR ⫽ target vessel revascularization; UA ⫽ unstable angina.
patients with heart rates ⬎65 beats/min compared with ⬍65 beats/min. These three studies demonstrate the feasibility of DSCT to reliably assess coronary artery stenosis, albeit at average heart rates that are ⬍70 beats/min. In another major technological development, 256-detector row CT, which permits whole-heart axial image acquisition in one gantry revolution, also was evaluated. With the use of motionsimulating coronary artery phantoms with varying reference diameters (1.5, 2, 3, and 4 mm) containing stenoses of varying severity (0.8 to 3.1mm) and shape, 256-detector row CT was observed to have less artifact than 64-detector row CT by conventional helical image acquisition (27). The reduced artifact, however, was not associated with significant accuracy difference between diameter and area measurements between 256-row compared with 64-row scanners. Further, the ability of 256-row MDCT to quantify subendocardial myocardial blood flow reduction was evaluated by George et al. (28). In a study of 19 patients with abnormal SPECT perfusion studies, adenosine-induced stress MDCT perfusion imaging was performed with 3 serial gantry revolutions
at 0.5 s. Using 3-mm short-axis reformations based upon a 17-segment myocardial model, they transmural perfusion ratio for each sector as the endocardial attenuation density/epicardial attenuation density, with ischemia defined as a total peripheral resistance ⬍0.8 in ⬎1 sector. Using ⬎50% coronary stenosis by MDCT within a geographical territory, George et al. (28) reported that the mean total peripheral resistance was 0.71 ⫾ 0.05 for abnormal sectors and 1.01 ⫾ 0.06 for normal sectors (p ⬍ 0.01). Sensitivity and specificity to detect a ⬎50% stenosis were similar for MDCT and SPECT (62% and 86%, respectively, vs. 62% and 71%, respectively, p ⫽ NS). These important studies emphasize the rapid advances that are occurring with MDCT technology, with improvements in temporal resolution and volume coverage now permitting image acquisition at higher heart rates and in shorter amounts of time, respectively. Nevertheless, these studies also highlight the current limitations of MDCT, and it is likely that reductions in partial volume effects of calcium or enhanced discriminatory ability to distinguish stenosis within small vessels will require improved spatial resolution.
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Predicting Coronary Events: Thinking Outside the Lumen. . .
Although most of CCTA studies to date have addressed the qualitative and quantitative diagnostic performance of CCTA for the detection of coronary stenoses compared with invasive angiography, numerous contemporary studies have begun to evaluate the role of CCTA in characterizing atherosclerotic plaque within the coronary vessel wall. Recent studies evaluating patients shortly after they have experienced acute coronary syndromes have demonstrated that the lesions responsible for acute events demonstrate expansive remodeling, low Hounsfield unit attenuation densities (⬍30 HU) representing necrotic cores, and spotty calcification. Conversely, stable plaques demonstrate greater density plaques that are generally not remodeled or negatively remodeled (29). To evaluate whether CCTA may identify plaques that may result in acute events subsequently, Motoyama et al. from the Fujita Health University, Japan, and the University of California, Irvine, analyzed CCTAs from 1,154 patients who were followed up for at least 12 months (range 12 to 51 months) (30). The degree of remodeling as well as the plaque composition was evaluated for all patients (Fig. 8). Positively remodeled and noncalcified plaques were characterized for plaque volume and consistency with Toshiba Medical System software, Tustin, California; lesions with previous PCI and target lesion for elective PCI were excluded. The plaque characteristics of lesions resulting in acute coronary syndrome (ACS⫹) were compared with those not resulting in ACS (ACS⫺). Ten of
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1,154 patients experienced ACS, as determined by CT. Of these, 7 had outwardly remodeled plaques and 6 had necrotic cores; 8 of these patients had both. The remaining 2 ACS⫹ patients with neither remodeling nor noncalcified plaque lucency demonstrated large calcification. In ACS⫺ patients, these 2 plaque characteristics were detected in 54 patients. Total plaque volume (291.9 ⫾ 269.0 mm3 vs. 152.8 ⫾ 78.5 mm3, p ⫽ 0.002), noncalcified plaque volume (26.0 ⫾ 50.0 mm3vs. 3.7 ⫾ 6.4 mm3, p ⫽ 0.0020), and maximum noncalcified plaque area in crosssectional images (4.7 ⫾ 5.6 mm2 vs. 1.3 ⫾ 1.7 mm2, p ⫽ 0.0004) was significantly larger in ACS⫹ group than ACS⫺ characteristics group. The study reconfirmed information derived from pathological studies, namely that lesions responsible for subsequent ACS possess larger plaque volume and that larger noncalcified plaque area and higher overall volume. In another presentation focused on plaque assessment, O’Donnell and Voros (31) reported the role of 18 F-fluorodeoxy glucose (FDG) positron emission tomographic imaging (PET) in the assessment of inflammation in coronary vasculature as a marker of plaque vulnerability (Fig. 9). They performed CCTA simultaneously with PET for anatomic delineation of the course of coronary vessels. O’Donnell and Voros (31) administered the Atkins diet and high-fat drinks to study subjects, followed by high-dose beta blockers to prevent FDG uptake by the myocardium and achieve relatively quiet background. In addition, they included only patients who underwent PCI either for ACS or stable coronary disease to allow for easy FDG localization (or absence
Figure 8. Coronary Computed Tomographic Angiography Reveals a Potentially Vulnerable Plaque in the Distal Right Coronary Artery (A) Which Was Responsible, As Seen in Conventional Angiogram (B), for Acute Coronary Event in Follow-Up
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Figure 9. FDG Uptake in Culprit Lesion Suggestive of Plaque Inflammation 18
F-fluorodeoxy glucose (FDG) uptake is demonstrated by positron emission tomographic imaging (PET) (A) at the site of stent implantation as depicted by coronary computed tomogrpahic angiography (B). MDCT ⫽ multidetector computed tomography; MI ⫽ myocardial infarction.
thereof) at the site of stent placement. The study hypothesis was that the patients presenting with ACS have inflamed plaques and, hence, significant FDG uptake at the stent site; in contrast, patients with stable disease do not have inflamed plaques and therefore, should not demonstrate FDG localization in stents. Twenty-five patients (ages 58 ⫾ 10 years, 70% male) were evaluated; 10 patients underwent PCI for ACS, 5 for chronic stable angina and the remaining 10 patients with previous stents underwent coronary angiography but did not require intervention (32). All patients received 13mCi 18F-FDG followed by PET (Siemens ECAT HR⫹; Siemens Medical Solutions. Malvern, Pennsylvania) at 3 h and 64-slice CCTA (Siemens Sensation; Siemens). Standardized uptake values were obtained for regions of interest, and target-to-background ratios were calculated. Target-to-background ratios at sites of stent implantation were greater for the ACS patients (2.3 ⫾ 0.6) compared with stable patients (1.8 ⫾ 0.5; p ⫽ 0.0004). Also, FDG uptake in the aortic root was greater in the ACS patients (3.6 ⫾ 1.3 vs. 2.5 ⫾ 0.7; p ⫽ 0.03). In addition, the glycolytic activity as measured by FDG uptake in the left main coronary vessel was greater for patients with ACS (2.4 ⫾ 0.6) than those who were stable (1.8 ⫾ 0.4; p ⫽ 0.001) patients. The result of this study suggest that the evaluation of inflammation in coronary vessels is possible with current-generation PET imaging and may be used for prognostication as well as to monitor the efficacy of therapeutic intervention.
Magnetic Resonance Imaging of the Vessel Wall: Gathering Wisdom From Periphery
Similarly, magnetic resonance imaging (MRI) has been evaluated for its ability to detect atheroscleroticmediated inflammation. Whereas gadolinium (Gd)-enhanced MRI cannot discriminate fibrosis from inflammation, small paramagnetic iron oxide (SPIO) may be engulfed by lesional macrophages and increase T1-signal intensity. In a study presented by O’Donnell and Voros (31), 5 patients underwent MRI (1.5-T Siemens Aavnto; Siemens) with a neck matrix coil before carotid endarterectomy. The T1-weighted turbo spin-echo black blood sequence was used with a repetition time to time-to-echo ⫽ 1,500 ms/10 ms, field of view 179 mm, matrix 320 ⫻ 320, and slice thickness 3 mm. Carotid arteries were imaged before and after SPIO and gadolinium administration. Both the postSPIO (7.8 vs. 5.8; p ⫽ 0.02) and Gd (9.3 vs. 5.8; p ⫽ 0.02) were greater than the pre-contrast signal. Iron was detected in the inflammation-rich plaques, and SPIO particles were found localized to the macrophages by transmission electron microscopy. Other MRI studies demonstrated reduction in atherosclerotic plaques with statins, such as the one presented by Oikawa et al. (32). The AHA Scientific Sessions 2007 were replete with first-of-their-kind investigations examining the diagnostic performance, clinical utility, and hypothesis-generating abilities of novel imaging strategies. These studies have begun to establish an exciting path that future studies can follow. Future work
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will help clarify which of the many imaging methods available at hand will be most beneficial in which clinical situations, and we look forward to those results.
REFERENCES
1. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. 2. Kereiakes DJ, Teirstein PS, Sarembock IJ, et al. The truth and consequences of the COURAGE trial. J Am Coll Cardiol 2007;50:1598 – 603. 3. Shaw LJ, Heller GV, Casperson P, et al., for the COURAGE Investigators. Gated myocardial perfusion single photon emission computed tomography imaging in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Trial. J Nucl Cardiol 2006;13:685–98. 4. Shaw LJ, Berman DS, Hartigan PH, et al. Differential improvement in stress myocardial perfusion ischemia following percutaneous coronary intervention as compared with optimal medical therapy alone: nuclear substudy results from the clinical outcomes using revascularization and aggressive drug evaluation (COURAGE) trial (abstr). Circulation 2007;116:II2628. 5. Gibbons RJ, Abrams J, Chatterjee K, et al., American College of Cardiology; American Heart Association Task Force on Practice Guidelines. ACC/ AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/ American heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 2003;41:159 – 68. 6. Schwartz RG, Pearson TA, Kalaria VG, et al. Prospective serial evaluation of myocardial perfusion and lipids during the first six months of pravastatin therapy. J Am Coll Cardiol 2003;42:600 –10. 7. Califf RM, Armstrong PW, Carver JR, D’Agostino RB, Strauss WE. Stratification of patients into high, medium, and low risk subgroups for purposes of risk factor management. J Am Coll Cardiol 1996;27:964 –1047. 8. Brindis RG, Douglas PS, Hendel RC, et al., American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group; American Society of Nuclear Cardiology; American Heart Association. ACCF/ ASNC appropriateness criteria for single-photon emission computed to-
Reprint requests and correspondence: Dr. Manuel D. Cer-
queira, Cleveland Clinic, Nuclear Medicine (Gb3), 9500 Euclid Avenue, Cleveland, Ohio 44195. E-mail: [email protected].
mography myocardial perfusion imaging (SPECT MPI): a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group and the American Society of Nuclear Cardiol ogy endorsed by the American Heart Association. J Am Coll Cardiol 2005; 46:1587– 605. 9. Senior R, Zabal M, Monaghan M, et al. Accurate detection of coronary artery disease by echocardiography using perflubutane polymer microspheres, a novel contrast agent: comparison with nuclear perfusion imaging in two phase three multicenter clinical trials (abstr). Circulation 2007;116:II546. 10. Douglas PS, Weyman AE, Lindner JR, Wei K. Contract echocardiography: past, present, and. . .future? J Am Coll Cardiol Img 2008;1:107–10. 11. Carrascosa PM, Capunay C, Carrascosa J, et al. Combined assessment of coronary artery stenosis and myocardial ischemia by rest-dipyridamole stress multidetector computed tomography (abstr). Circulation 2007;116: II656. 12. Shapiro MD, Nieman K, Nomura CH, et al Cardiac computed tomography for prediction of myocardial viability after reperfused acute myocardial infarction (abstr). Circulation 2007;116:II563. 13. Sato A, Nozato T, Hikita H, et al. Clinical value of multidetector computed tomography for early evaluation of myocardial viability, left ventricular remodeling and prognosis after acute myocardial infarction (abstr). Circulation 2007;116:II562. 14. Miller JM, Rochitte CE, Dewe M, et al. Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography (CORE64): results of a multicenter, international trial to assess diagnostic accuracy compared with conventional coronary angiography (abstr). Circulation 2007;116:II2630. 15. Abdellaoui M, Ohanessian A, Lefevre T, et al. Comparison of early patency of off-pump and on-pump multivessel coronary artery bypass surgery assessed by MDCT (abstr). Circulation 2007; 116:II343. 16. Ostrum MP, Yang E, Mao S, Gopal A, Ahmadi N, Budoff MJ. Mortality incidence and the severity of coronary atherosclerosis assessed by CT an-
giography (abstr). Circulation 2007; 116:II771. 17. Van Werkohoven J, Schiujf JD, Gaemperli O, et al. Prognostic value of multi-slice computed tomography and gated single photon emission computed tomography in a cohort of 426 patients with known or suspected coronary artery disease (abstr). Circulation 2007;116:II771. 18. Kunimasa T, Sato Y, Matsumoto N, et al. Prognostic value of nonobstructive CT low-dense coronary artery plaques detected by multislice computed tomography (abstr). Circulation2007;116:II770. 19. Ahmadi N, Gopal A, Ramirez J, et al. Clinical utility of cardiac CT angiography: 40 month follow up of ambulatory patients (abstr). Circulation 2007;116:II343. 20. Aggarwal NR, Knickelbine T, Tande A, Solftus L, Lesser J, Schwartz RS. Clinical outcome in patients with noncalcified coronary plaque detected by multi slice computed tomography: risk factors, stenosis and 34-month clinical outcome (abstr). Circulation 2007;116:II656. 21. Steinbigler P, Bohme E, Weber C, Czernik A, Buck J, Haberl R. Exclusion of coronary artery stenosis by noninvasive coronary angiography using multislice computed tomography determines a good long-term prognosis in patients with chest pain—follow-up study in 1017 patients (abstr). Circulation 2007;116:II341–2. 22. Azevedo C, Spoti M, Bezerra S, et al. Coronary multidetector computed tomography in the prognostic assessment of patients with equivocal or mildly abnormal non-invasive cardiac stress tests (abstr). Circulation 2007;116: II574. 23. Aldrovandi A, Romano M, Seitun S, et al. Prognostic value of coronary computed tomography in patients with suspected coronary artery disease in a large prospective single center clinical experience with 2 years follow-up (abstr). Circulation 2007; 116:II573. 24. Burgstahler C, Brodoefel H, Reimann A, et al. Dual-source CT in noninvasive coronary artery angiography: effect of heart rate, heart rate variability and calcification on image quality and diagnostic accuracy in an unselected patient population (abstr). Circulation 2007;116:II408.
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25. Rixe J, Conradi G, Rolf A, Hamm C, Dill T. Diagnostic accuracy of dual source-MDCT for detection of significant coronary artery stenoses in comparison to invasive coronary angiography (abstr). Circulation 2007;116: II692. 26. Leber A, Ovrehus K, Tittus J, Johnson T, Becker C, Becker A. Noninvasive coronary angiography by dual source computed tomography in patients with an intermediate pretest likelihood for coronary artery disease (abstr). Circulation 2007;116:II574. 27. Kitagawa K, Arbab-Zadeh A, Hannon KM, George RT, Lima JA, Lardo AC. Comparison of 256 ⫻ 0.5mm and 64 ⫻ 0.5mm multidetector computed tomography image
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quality and accuracy in a customdesigned, motion-simulating phantom of coronary artery stenosis (abstr). Circulation 2007;116:II408 –9. 28. George RT, Yousuf O, Kitagawa K, Chang HJ, Bluemke DA, Lardo AC, Lima JA. Quantification of myocardial perfusion in patients using 256row multidetector computed tomography: evaluation of endocardial vs. epicardial blood flow (abstr). Circulation 2007;116:II563. 29. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 2007;50:319 –26. 30. Rogers IS, Figueroa AL, Nasir K, et al. Assessment of coronary segment
inflammation with combined 18fluorodeoxyglucose positron emission tomography and 64-slice multidetector computed tomography (abstr). Circulation 2007;116:II410. 31. O’Donnell R, Voros S. T1-weighted turbo spin echo cardiovascular magnetic resonace imaging shows a significant increase in signal after SPIO administration in human carotid atherosclerotic plaques (abstr). Circulation 2007;116:II560. 32. Oikawa M, Yuan C, Underhill H, et al. Time course of change in plaque composition associated with rosuvastatin therapy as assessed by highresolution magnetic resonance imaging (abstr). Circulation 2007;116: II441.
VOL. 1, NO. 2, 2008
© 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/08/$34.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2008.01.012
IMAGING EXCERPTS FROM SCIENTIFIC MEETINGS
Imaging Highlights of the American Heart Association 2007 Scientific Sessions James K. Min, MD, FACC,* Leo Hofstra, MD,† Swaminatha V. Gurudevan, MD,‡ Manuel D. Cerqueira, MD, FACC, FAHA, FASNC§ New York, New York; Maastricht, the Netherlands; Irvine, California; and Cleveland, Ohio
Of the 3,780 abstracts accepted for presentation at the American Heart Association (AHA) Scientific Sessions 2007 in Orlando, 206 belonged to the cardiovascular imaging category. The following abstracts can be considered the imaging highlights of 2007. From session to session and hall to hall in our quest to get the best possible abstracts to you, a clear emphasis was placed this year on computed tomographic angiography of the coronary arteries and on multimodality imaging of atherosclerotic plaques. These techniques place give us hope for a preventive rather than reactive approach and, if well characterized in the ensuing years, they should prove worthy for better characterization of coronary vessel walls in individuals at risk. Seeking COURAGE From the Wizard of Oz. . .
Considerable controversy exists regarding the lack of added benefit reported for percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) when compared with OMT alone within the COURAGE (Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation) trial (1). This randomized controlled trial enrolled 2,287 patients who were followed for 4.6 years, with no differences identified by treatment strategy for the primary end point of death or acute myocardial infarction (1). Although one can argue the limitations of any randomized trial (2), the results of the
From the *Weill Medical College of Cornell University, New York, New York; †Academic University of Maastricht, Maastricht, the Netherlands; ‡University of California Irvine School of Medicine, Irvine; and the §Cleveland Clinic Foundation, Cleveland, Ohio. Dr. Min is on the Speakers’ Bureau of and is a consultant for GE Healthcare. Manuscript received 23 January 2008; accepted January 30, 2008.
COURAGE trial suggested to us that, in chronic, stable angina patients, PCI may be initially safely deferred. Nearly a decade ago, when planning the COURAGE trial, the executive committee had decided to include several substudies that included evaluation of the role of ischemia with the use of quantitative myocardial perfusion single-photon emission computed tomography (SPECT) imaging (MPI-SPECT) (3). These substudies included evaluating prognosis in relation to pre-treatment MPI assessment, utility of MPI to discriminate optimal treatment strategies for patients with recurrent angina, and the role of sequential ischemia testing by MPI (3). The MPI substudy of the COURAGE trial was reported at the late breaking clinical trials and included serial MPI evaluation in 314 of the 2,287 patients (4). Serial MPI in patients included a pre-treatment and 18-month follow-up MPI study to examine the impact of intercurrent treatment on myocardial ischemia. Although there was no definitive rationale for the timing of the follow-up scan, numerous key opinion leaders in the field of cardiovascular medicine agreed by expert consensus on this follow-up time. The opinion of the nuclear substudy leadership within COURAGE was that an 18-month window would permit sufficient time for the effects of medical therapy to be observed as well as to be beyond the window of in-stent restenosis. For entry into the MPI COURAGE substudy, patients were required to exhibit evidence of ischemia upon study entry, as determined by the local clinical investigator. A total of 25 of the 50 COURAGE sites participated in this substudy and included sites with large-volume MPI laboratories that frequently rely on perfusion imaging data to guide therapeutic decision making. The
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Ischemia Reduction ≥5%
50%
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Figure 1. Percent of Patients in the COURAGE MPI Substudy With Ischemia Reduction >5% Myocardium (n ⴝ 314) COURAGE ⫽ Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation; OMT ⫽ optimal medical therapy; PCI ⫽ percutaneous coronary intervention.
First, it reflected a selected subset of only 14% of the COURAGE-enrolled patients, and myocardial perfusion single-photon emission computed tomography (MPS) was not mandated within COURAGE, so this sample thereby reflects a limited understanding of the role of imaging in therapeutic decision-making. Second, any association of prognosis as it relates to MPI-identified ischemia and treatment strategy of angina patients cannot be established by the COURAGE MPI substudy because of a lack of power. These results, then, should be viewed as useful primarily for hypothesis-generating purposes or as helpful for devising future clinical trials. Definitive statements about the benefit of PCI ⫹ OMT over OMT alone 100%
Ischemia Reduction ≥5%
requirement that study entry be limited to those patients with ischemia was based upon American College of Cardiology (ACC)/AHA guidelines for targeting anatomic stenosis that may benefit from PCI (5). Furthermore, previous smaller series have revealed demonstrable reductions in provocative ischemia with medical therapy, as noted in a recent review (3). In one report by Schwartz et al. (6), nearly one-half of patients with chronic coronary disease exhibited a sizeable reduction in ischemia after 6 months of statin therapy. Thus, at the study’s initiation, it was unclear whether reductions in MPI-identified ischemia would be favored in either of the 2 arms. Shaw et al. (4) presented the results of this substudy, reporting a marked reduction in ischemia with PCI ⫹ OMT when compared with OMT alone. In fact, 33% of the PCI ⫹ OMT patients exhibited a reduction in ischemia that encumbered 5% or more of the myocardium based on quantitative MPI, as compared with only 20% for those enrolled in the OMT arm (p ⫽ 0.004) (Fig. 1). This threshold of a change in ischemia ⱖ5% of the myocardium was chosen because of its prognostic significance and the fact that it exceeded inter-test repeatability (4). Although an inclusion criterion limited entry of patients to those with ischemia, the COURAGE substudy patients, on average, had only mild ischemia (approximately 8% of the myocardium being ischemic) before treatment. Thus, a greater benefit was anticipated for those patients with a greater risk of ischemia (i.e., moderate-to-severe ischemia or ⱖ10% of the myocardium). In keeping with this expectation, the results from this substudy revealed that nearly 80% of patients with moderate-to-severe severe pretreatment ischemia exhibited a marked ischemia reduction of ⱖ5% of the myocardium with PCI ⫹ OMT as compared with only 52% of OMT patients (p ⫽ 0.007) (Fig. 2). Thus, it appears that this latter threshold may prove to be an effective entry criterion for future randomized trials. These latter results are consistent with the tenet in therapeutic intervention that greater-risk patients receive a greater proportional benefit with intervention (7). To that extent, future work in this area would be interesting to examine any added benefit with PCI over OMT. The COURAGE MPI substudy examined the primary end point of ischemia reduction and was underpowered to examine changes in prognosis. Readers should, therefore, adopt these results cautiously and realize the limitations of the report.
80%
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Figure 2. Percent of Patients in the COURAGE MPI Substudy With Ischemia Reduction >5% Myocardium Who Had Moderate-to-Severe Pre-Treatment Ischemia Abbreviations as in Figure 1.
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as they relate to long-term outcome cannot be inferred from this substudy. Third, this substudy was powered to examine an overall effect of changes in ischemia and did not consider any key patient subsets, including those with previous myocardial infarction, with diabetes, who were women, or those with impaired left ventricular function. This latter point is critical for clinicians desiring to implement this information into their daily practice. Finally, the COURAGE MPI substudy results do not endorse routine 1-year MPS studies. That is, patients who are angina-free at 1 year do not require additional, unnecessary MPS. These results when using serial MPI remain outside of standards put forth in the recent appropriateness criteria (8). Thus, we await additional guidance from updated documents from the ACC to evaluate the role of serial MPI for patients with chronic coronary disease. The COURAGE MPI substudy results are groundbreaking in that they reflect a decade-long inquiry by the COURAGE investigators to move MPI beyond the role of risk stratification into a realm of fully integrated clinical-decision making. Because reductions in ischemia were associated with improvements in angina, the COURAGE MPI substudy now establishes the heretofore-unmet standard of effectiveness in cardiovascular imaging, namely, the demonstration of improved health benefits in patients undergoing MPI-guided therapy. Additional clinical trials are still necessary to elicit the role of cardiac imaging for guidance of therapeutic decision making in other areas of cardiovascular medicine. To date, cardiac imaging trials have been generally poorly funded, and the lion’s share of evidence has been derived from prospective, observational registries. If any single take-home lesson was learned by the COURAGE substudy, it is that imaging can be an important, if not critical, component of a clinical trial. Trialists embarking on future controlled clinical studies can now consider the benefit of cardiovascular imaging in the context of not only future risk stratification, but also of improving health outcomes, especially as it relates to its use as an intermediate outcome. Along the line of myocardial ischemia assessment, the results of a multicenter Phase III trial that used contrast echocardiography with a synthetic biodegradable ultrasound contrast material, perflubutane polymer microspheres (Imagify, Acusphere, Watertown, Massachusetts), were also presented at the AHA 2007 Scientific Sessions (9).
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Presented by Roxy Senior, on behalf of investigators of RAMP (the Real-time Assessment of Myocardial Perfusion Imaging)-1 (n ⫽ 285) and RAMP-2 (n ⫽ 377 patients) phase III trials, these studies took place at 28 international centers in 662 patients presenting with angina. The primary analyses focused on the safety and efficacy of the perflubutane polymer microspheres. These data were compared with quantitative myocardial perfusion studies performed with 99mTc-labeled perfusion tracers imaging at rest and after dipyridamole stress. All images were inspected for the presence of wall motion abnormalities and/or perfusion defects by independent blinded readers, with diagnostic accuracy of perflubutane polymer microsphere ischemia detection determined by quantitative coronary angiography in a non-inferiority and superiority analysis. In the RAMP-1 and -2 studies, the prevalence of significant coronary artery disease was 44% and 58% of patients, respectively. The contrast echocardiography results were demonstrated to be either noninferior or superior to nuclear imaging for accuracy, sensitivity, and specificity. Except for a lone case of hypersensitivity in one study patient, no side effects of the new contrast agent were observed. In this issue of JACC: Cardiovascular Imaging, the results of OPTIMIZE trial highlighting the role of ultrasound contrast for stress testing also are presented. Readers are, however, cautioned that the use of contrast in the stress setting is not an approved indication and is considered off-label. Particular care should be given to the use of contrast echocardiography, given the recent black box warning for the use of ultrasound contrast agents (10). Similarly, Carrascosa et al. (11) studied 47 patients who underwent both stress/rest 99mTc sestamibi SPECT and rest-dipyridamole stress multidetector computed tomography (MDCT) cardiac scans. Overall sensitivity and specificity to detect stress-induced ischemia as defined by reduction in myocardial contrast enhancement was 77% and 99%, respectively, compared with SPECT. Reductions of myocardial contrast enhancement on MDCT scans at rest were associated with high a sensitivity and specificity of 96% and 98%, respectively, for the detection of myocardial scar. On the other hand, Shapiro et al. (12) examined the significance of hypoattenuated left ventricular myocardium in patients after a first ST-segment elevation myocardial infarction. Using 64-slice coronary computed tomographic angiography (CCTA), 17 patients treated with primary percutaneous coronary intervention (average door-to-
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balloon time 81 ⫾ 34 min) were evaluated with both CCTA and cardiac magnetic resonance imaging (CMR; mean 2.9 ⫾ 1.0 days after ST-segment elevation myocardial infarction) and a follow-up CMR at 6 months. Of 680 myocardial segments evaluated, 204 (30%) demonstrated a hypoattenuation pattern that was defined as a perfusion defect. Transmurality of perfusion defects, as imaged by CCTA, were inversely proportional to left ventricular recovery. Improved regional left ventricular function score, when assessed with CMR, was associated with segments with ⬍25% transmurality (42 of 65, 65%) but not ⬎75% transmurality of PD (2 of 23, 9%). On the basis of these preliminary results, CCTA holds promise in our ability to assess myocardial viability and predict left ventricular recovery after successful revascularization in patients presenting with first acute ST-segment elevation myocardial infarction. In a parallel study of 52 consecutive patients presenting with first acute myocardial infarction, noncontrast 64-row CCTA was performed immediately after iodine exposure from selective coronary angiography (13). The CCTA scans were compared with electrocardiogram-gated thallium-201 SPECT scans within 5 days and 6 months after onset of myocardial infarction. Hyperattenuated areas were considered areas of myocardial delayed enhancement and transmurality and were compared with angiographic, SPECT, and clinical data at 6 months. Three groups were identified: group A demonstrated transmural delayed enhancement (DE) (n ⫽ 18) (Fig. 3), group B demonstrated subendocardial DE (n ⫽ 20), and group C demonstrated no DE (n ⫽ 14). Group A demonstrated greater peak creatine kinase, myocardial band (483 ⫾ 286 IU/ml vs. group B, 223 ⫾ 155 IU/ml and group C, 129 ⫾ 117 IU/ml, respectively, p ⫽ 0.0017) with lower incidences of myocardial blush grade 3 (22% vs, group B 67% and group C 75%, p ⫽ 0.0071) and left ventricular ejection fraction (41 ⫾ 8% vs. group B 53 ⫾ 13% and group C 62 ⫾ 11%, p ⬍ 0.001). Furthermore, during the 6-month period, left ventricular end-diastolic volume increased significantly (110 ⫾ 25 mm3 to 125 ⫾ 21 mm3, p ⫽ 0.042) in Group A, whereas rates of rehospitalization for heart failure (p ⫽ 0.0121) more often were observed. CORE-64: Inching Closer to the Core Expectation!
Coronary computed tomographic angiography continues to be evaluated as an exciting new
Figure 3. Transmural Hyperenhancement by 64-Slice Computed Tomography in Group A Adapted from Sato et al. (12).
diagnostic tool for the assessment of obstructive coronary disease. Although a large number of single-center studies have been reported, the CORE-64 (Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography using 64 Detectors) study, presented at the AHA 2007 Scientific Sessions, represented the first prospective, multicenter study to compare 64-slice CCTA to standard quantitative coronary arteriography (Fig. 4) (14). This study, undertaken in 9 centers in 7 countries, enrolled 291 patients (⬎40 years of age; calcium scores ⬍600) who first underwent CCTA followed by clinically indicated conventional coronary angiography, with a primary end point of diagnostic ability of 64-slice CCTA to identify patients with significant coronary artery disease (CAD). All nonstented segments ⬎1.5 mm were assessed by 2 independent core laboratories with 2 blinded readers per laboratory. Coronary artery stenosis ⬎50% by quantitative coronary angiography (QCA) was considered significant, and patients were followed clinically for cardiovascular events, including revascularization. Coronary artery segments were evaluable in 97% of 291 patients, and the prevalence of significant CAD by QCA was 56%. On a per-patient based analysis, quantitative analysis of stenosis by CCTA revealed an area under the curve of 0.93 (95% confidence interval [CI] 0.90 to 0.96) in
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Patients >40 yrs, suspected CAD, referred for clinical cath
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Figure 4. Study Design of the CORE-64 Study Ca ⫽ calcium; CAD ⫽ coronary artery disease; MDCT ⫽ multidetector computed tomography; MDCTA ⫽ multidetector computed tomographic angiography.
comparison with QCA; the overall sensitivity of quantitative CCTA for detection of a significant stenosis ⬎50% was 0.85 (95% CI 0.79 to 0.90) and specificity 0.90 (95% CI 0.83 to 0.94) (Fig. 5). Given the disease prevalence rate of 56%, the positive and negative predictive values were 0.91 and 0.83, respectively. Interestingly, on the patient level, CCTA demonstrated an equivalent ability to
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Figure 5. ROC Curve and Diagnostic Test Performance and Characteristics of 64-Slice Coronary Computed Tomographic Angiography in the CORE-64 Study CI ⫽ confidence interval; CORE-64 ⫽ Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography using 64 Detectors; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value; ROC ⫽ receiveroperator characteristics.
identify the need for coronary revascularization, when compared with QCA. The diagnostic performance of CCTA on “per-patient basis” appeared to be better as compared to the assessment on “pervessel basis” (Fig. 6). Given the aforementioned results, the study concluded that 64 detector CCTA can be used to evaluate symptomatic patients for significant CAD as well as the potential need for revascularization procedures. This late-breaking study, supported by Toshiba Medical Systems and Bracco, was presented at the AHA 2007 by Julie Miller, MD, of Johns-Hopkins Medical Center on behalf of the CORE-64 investigators. Although this study confirmed the strong performance of CCTA imaging, particularly a strong positive predictive value, more evidence is still necessary for appropriateness of indications of CCTA in clinical practice. However, the CORE-64 study moves the field closer to the “core” goal of eventually replacing standard invasive coronary angiography by a noninvasive test as a diagnostic tool. In another interesting diagnostic accuracy study, Abdellaoui et al. (15) from the Institut Hospitalier Jacques Cartier, France, investigated the role of CCTA in the detection of coronary artery bypass graft patency. This study evaluated the graft patency rate in the early post-operative period after off-pump bypass grafts and compared the patency rates with standard on-pump procedures. Of the 134 enrolled patients (median age, 66 years), 11 were excluded because of arrhythmias or tachycardia in despite beta blockers; in 15 patients, CCTA could not be performed because of the inaccessibility of CCTA at the time of discharge. Of the remaining 108 patients, CCTA findings were compared in 188 grafts from 69 patients after on-pump surgery, with 125 grafts in 39 patients after an off-pump procedure. The overall graft patency was 98%, including 97% on-pump and 98% off-pump procedures. On the other hand, in a 5-year follow-up of 2,971 consecutive primarily low- and intermediaterisk chest pain patients, all-cause mortality was examined in relation to obstructive plaque identified with CCTA (Fig. 7) (16). Coronary artery plaque was assessed by the absence of detectable plaque, nonobstructive plaque, and obstructive plaque. Compared with adults with no evident coronary artery plaque, adults with obstructive coronary plaque were much more likely to die if 1-vessel obstructive plaque (risk ratio [RR] 5.6, 95% CI 1.56 to 18.9, p ⫽ 0.01), 2-vessel obstructive plaque (RR 6.9 95% CI 1.6 to 32.9, p ⫽ 0.03), or 3-vessel
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1.0 0.9 0.8
Sensitivity
obstructive plaque (RR 26.0, 95% CI 3.6 to 92.1, p ⫽ 0.001) was present. Importantly, even the presence of nonobstructive plaque conferred increased risk of mortality (RR 2.9, 95% CI 1.6 to 11.5, p ⫽ 0.01). In keeping with other studies, the 5-year rate of death for chest pain patients without detectable coronary artery plaque by CCTA was low (1.8%). In addition to this long-term follow-up, several investigations were presented that examined the prognostic value of CCTA to detect other end points, including major adverse cardiac events (Table 1) (17–23).
0.7
ROC Area
0.6
Patient = 0.93 [0.90-0.96] Vessel = 0.91 [0.88-0.93]
0.5 0.4 0.3 0.2 0.1 0.0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
CT Angiography Technology: Faster and Better
The 2007 Scientific Sessions examined 2 recently introduced features to MDCT, namely improved temporal resolution and increased numbers of detector rows, demonstrating the feasibility of CCTA use in individuals with higher heart rates and with less artifact, respectively. Burgstahler et al. (24) studied the diagnostic accuracy of dual-source CT (DSCT) scanners with improved 83-ms temporal resolution in 100 consecutive patients with known or suspected CAD, in which image quality using DSCT was evaluated weighing the impact of heart rate, heart rate variability and calcification. The average heart rate was 64.0 ⫾ 13.2 beats/min, mean heart rate variability 23.6 ⫾ 36.2 beats/examination, and mean coronary artery calcium score 786.5 ⫾ 965.9 Agatston units. Of 90.2% segments that were evaluable, per-patient and -segment sensitivity compared with quantitative coronary angiography, specificity, and positive and negative predictive values were 100%, 81.5%, 93.6%, and 100% and 91.1%, 92.0%, 75.4%, and 97.5%, respectively. Notably, image quality was unaffected by increasing heart rate but was impacted by heart rate variability and coronary artery calcification. Diagnostic accuracy was unrelated to either heart rate or variability, but only to coronary artery calcification. In a similar study of 65 consecutive patients with suspected CAD with an average heart rate of 68 ⫾ 9 beats/min, per-patient and per-segment accuracy compared with quantitative coronary angiography for sensitivity, specificity, and positive and negative predictive values were 100%, 83.3%, 86.9%, and 100% and 98.3%, 96.7%, 86.6%, and 99.9%, respectively (25). Notably, only 2 of 1,160 coronary artery segments were unevaluable (0.17%). In this cohort,
False Positive Rate Sensitivity
Specificity
PPV
NPV
0.85 0.76
0.90 0.93
0.91 0.82
0.83 0.89
Patient All Vessels
Figure 6. Comparison of “Per-Patient” and “Per-Vessel” Performance by 64-Slice Coronary Computed Tomographic Angiography in the CORE-64 Study Abbreviations as in Figure 5.
the average coronary artery calcium score was low (100 ⫾ 560 Agatston units), which may explain the improved specificity. Finally, Leber et al. (26) examined 130 patients with intermediate likelihood for significant coronary artery disease who were referred for DSCT and invasive coronary angiography. Compared with invasive coronary angiography, DSCT resulted in a sensitivity, specificity, and positive predictive value of 100%, 96%, and 76%, respectively. Notably, accuracy to detect a ⬎75% stenosis did not differ in
30 25 Relative Risk
20 15 10 5 0
Non-obstructive
1V
2V
3V
Figure 7. Relative Risk for All-Cause Mortality by Number of Epicardial Coronary Artery Vessels With Nonobstructive, 1-, 2-, or 3-Vessel Obstructive Plaque as Identified With Computed Tomography
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Table 1. Studies Evaluating the Prognostic Value of CCTA CCTA Predictor
Clinical End Point
Van Werkhoven et al. (17)
Author (Ref. #)
426
⬎50% obstructive plaque ⫹ abnormal MPI versus ⬍50% plaque ⫹ normal MPI
60-day cardiac death, nonfatal MI, UA, TVR
39% vs. 8%
Kunimasa et al. (18)
760
Nonobstructive low density plaques by CCTA
MI, UA, cardiac death
MI (0.94% vs. 0.05%), UA (1.13% vs. 0.64%), ACS (2.08% vs. 0.7%), cardiac death (0.37% vs. 0.23%)
0.002
Ahmadi et al. (19)
493
Obstructive plaque by CCTA
40-month follow-up of MI or death
100% event free survival for patients with no obstructive plaque; HR 16.6 (95% CI 4.9 to 55.2)
0.0001
Aggarwal et al. (20)
506
No plaque versus nonobstructive noncalcified plaque
34-month follow-up of TVR
0% versus 40%
1,017
Obstructive stenosis
602 days for all-cause death
Exclusion of stenosis with low risk of death
218 abnormal or equivocal stress test
Obstructive stenosis
8 months cardiac death, MI, TVR, UA
100% event-free survival for no plaque; HR 12.59 for obstructive stenosis
0.01
No coronary stenosis versus coronary stenosis‘
2-year cardiac death, MI, UA, TVR
100% event-free survival with no coronary stenosis
N/A
Steinbigler et al. (21)
Azevedo et al. (22)
Aldrovandi et al. (23)
No. of Patients
187
Results
p Value ⬍0.001
⬍0.05
ACS ⫽ acute coronary syndromes; CCTA ⫽ coronary computed tomographic angiography; CI ⫽ confidence interval; HR ⫽ hazard ratio; MI ⫽ myocardial infarction; MPI ⫽ myocardial perfusion single-photon emission computed tomography imaging; N/A ⫽ not applicable; TVR ⫽ target vessel revascularization; UA ⫽ unstable angina.
patients with heart rates ⬎65 beats/min compared with ⬍65 beats/min. These three studies demonstrate the feasibility of DSCT to reliably assess coronary artery stenosis, albeit at average heart rates that are ⬍70 beats/min. In another major technological development, 256-detector row CT, which permits whole-heart axial image acquisition in one gantry revolution, also was evaluated. With the use of motionsimulating coronary artery phantoms with varying reference diameters (1.5, 2, 3, and 4 mm) containing stenoses of varying severity (0.8 to 3.1mm) and shape, 256-detector row CT was observed to have less artifact than 64-detector row CT by conventional helical image acquisition (27). The reduced artifact, however, was not associated with significant accuracy difference between diameter and area measurements between 256-row compared with 64-row scanners. Further, the ability of 256-row MDCT to quantify subendocardial myocardial blood flow reduction was evaluated by George et al. (28). In a study of 19 patients with abnormal SPECT perfusion studies, adenosine-induced stress MDCT perfusion imaging was performed with 3 serial gantry revolutions
at 0.5 s. Using 3-mm short-axis reformations based upon a 17-segment myocardial model, they transmural perfusion ratio for each sector as the endocardial attenuation density/epicardial attenuation density, with ischemia defined as a total peripheral resistance ⬍0.8 in ⬎1 sector. Using ⬎50% coronary stenosis by MDCT within a geographical territory, George et al. (28) reported that the mean total peripheral resistance was 0.71 ⫾ 0.05 for abnormal sectors and 1.01 ⫾ 0.06 for normal sectors (p ⬍ 0.01). Sensitivity and specificity to detect a ⬎50% stenosis were similar for MDCT and SPECT (62% and 86%, respectively, vs. 62% and 71%, respectively, p ⫽ NS). These important studies emphasize the rapid advances that are occurring with MDCT technology, with improvements in temporal resolution and volume coverage now permitting image acquisition at higher heart rates and in shorter amounts of time, respectively. Nevertheless, these studies also highlight the current limitations of MDCT, and it is likely that reductions in partial volume effects of calcium or enhanced discriminatory ability to distinguish stenosis within small vessels will require improved spatial resolution.
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Predicting Coronary Events: Thinking Outside the Lumen. . .
Although most of CCTA studies to date have addressed the qualitative and quantitative diagnostic performance of CCTA for the detection of coronary stenoses compared with invasive angiography, numerous contemporary studies have begun to evaluate the role of CCTA in characterizing atherosclerotic plaque within the coronary vessel wall. Recent studies evaluating patients shortly after they have experienced acute coronary syndromes have demonstrated that the lesions responsible for acute events demonstrate expansive remodeling, low Hounsfield unit attenuation densities (⬍30 HU) representing necrotic cores, and spotty calcification. Conversely, stable plaques demonstrate greater density plaques that are generally not remodeled or negatively remodeled (29). To evaluate whether CCTA may identify plaques that may result in acute events subsequently, Motoyama et al. from the Fujita Health University, Japan, and the University of California, Irvine, analyzed CCTAs from 1,154 patients who were followed up for at least 12 months (range 12 to 51 months) (30). The degree of remodeling as well as the plaque composition was evaluated for all patients (Fig. 8). Positively remodeled and noncalcified plaques were characterized for plaque volume and consistency with Toshiba Medical System software, Tustin, California; lesions with previous PCI and target lesion for elective PCI were excluded. The plaque characteristics of lesions resulting in acute coronary syndrome (ACS⫹) were compared with those not resulting in ACS (ACS⫺). Ten of
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1,154 patients experienced ACS, as determined by CT. Of these, 7 had outwardly remodeled plaques and 6 had necrotic cores; 8 of these patients had both. The remaining 2 ACS⫹ patients with neither remodeling nor noncalcified plaque lucency demonstrated large calcification. In ACS⫺ patients, these 2 plaque characteristics were detected in 54 patients. Total plaque volume (291.9 ⫾ 269.0 mm3 vs. 152.8 ⫾ 78.5 mm3, p ⫽ 0.002), noncalcified plaque volume (26.0 ⫾ 50.0 mm3vs. 3.7 ⫾ 6.4 mm3, p ⫽ 0.0020), and maximum noncalcified plaque area in crosssectional images (4.7 ⫾ 5.6 mm2 vs. 1.3 ⫾ 1.7 mm2, p ⫽ 0.0004) was significantly larger in ACS⫹ group than ACS⫺ characteristics group. The study reconfirmed information derived from pathological studies, namely that lesions responsible for subsequent ACS possess larger plaque volume and that larger noncalcified plaque area and higher overall volume. In another presentation focused on plaque assessment, O’Donnell and Voros (31) reported the role of 18 F-fluorodeoxy glucose (FDG) positron emission tomographic imaging (PET) in the assessment of inflammation in coronary vasculature as a marker of plaque vulnerability (Fig. 9). They performed CCTA simultaneously with PET for anatomic delineation of the course of coronary vessels. O’Donnell and Voros (31) administered the Atkins diet and high-fat drinks to study subjects, followed by high-dose beta blockers to prevent FDG uptake by the myocardium and achieve relatively quiet background. In addition, they included only patients who underwent PCI either for ACS or stable coronary disease to allow for easy FDG localization (or absence
Figure 8. Coronary Computed Tomographic Angiography Reveals a Potentially Vulnerable Plaque in the Distal Right Coronary Artery (A) Which Was Responsible, As Seen in Conventional Angiogram (B), for Acute Coronary Event in Follow-Up
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Figure 9. FDG Uptake in Culprit Lesion Suggestive of Plaque Inflammation 18
F-fluorodeoxy glucose (FDG) uptake is demonstrated by positron emission tomographic imaging (PET) (A) at the site of stent implantation as depicted by coronary computed tomogrpahic angiography (B). MDCT ⫽ multidetector computed tomography; MI ⫽ myocardial infarction.
thereof) at the site of stent placement. The study hypothesis was that the patients presenting with ACS have inflamed plaques and, hence, significant FDG uptake at the stent site; in contrast, patients with stable disease do not have inflamed plaques and therefore, should not demonstrate FDG localization in stents. Twenty-five patients (ages 58 ⫾ 10 years, 70% male) were evaluated; 10 patients underwent PCI for ACS, 5 for chronic stable angina and the remaining 10 patients with previous stents underwent coronary angiography but did not require intervention (32). All patients received 13mCi 18F-FDG followed by PET (Siemens ECAT HR⫹; Siemens Medical Solutions. Malvern, Pennsylvania) at 3 h and 64-slice CCTA (Siemens Sensation; Siemens). Standardized uptake values were obtained for regions of interest, and target-to-background ratios were calculated. Target-to-background ratios at sites of stent implantation were greater for the ACS patients (2.3 ⫾ 0.6) compared with stable patients (1.8 ⫾ 0.5; p ⫽ 0.0004). Also, FDG uptake in the aortic root was greater in the ACS patients (3.6 ⫾ 1.3 vs. 2.5 ⫾ 0.7; p ⫽ 0.03). In addition, the glycolytic activity as measured by FDG uptake in the left main coronary vessel was greater for patients with ACS (2.4 ⫾ 0.6) than those who were stable (1.8 ⫾ 0.4; p ⫽ 0.001) patients. The result of this study suggest that the evaluation of inflammation in coronary vessels is possible with current-generation PET imaging and may be used for prognostication as well as to monitor the efficacy of therapeutic intervention.
Magnetic Resonance Imaging of the Vessel Wall: Gathering Wisdom From Periphery
Similarly, magnetic resonance imaging (MRI) has been evaluated for its ability to detect atheroscleroticmediated inflammation. Whereas gadolinium (Gd)-enhanced MRI cannot discriminate fibrosis from inflammation, small paramagnetic iron oxide (SPIO) may be engulfed by lesional macrophages and increase T1-signal intensity. In a study presented by O’Donnell and Voros (31), 5 patients underwent MRI (1.5-T Siemens Aavnto; Siemens) with a neck matrix coil before carotid endarterectomy. The T1-weighted turbo spin-echo black blood sequence was used with a repetition time to time-to-echo ⫽ 1,500 ms/10 ms, field of view 179 mm, matrix 320 ⫻ 320, and slice thickness 3 mm. Carotid arteries were imaged before and after SPIO and gadolinium administration. Both the postSPIO (7.8 vs. 5.8; p ⫽ 0.02) and Gd (9.3 vs. 5.8; p ⫽ 0.02) were greater than the pre-contrast signal. Iron was detected in the inflammation-rich plaques, and SPIO particles were found localized to the macrophages by transmission electron microscopy. Other MRI studies demonstrated reduction in atherosclerotic plaques with statins, such as the one presented by Oikawa et al. (32). The AHA Scientific Sessions 2007 were replete with first-of-their-kind investigations examining the diagnostic performance, clinical utility, and hypothesis-generating abilities of novel imaging strategies. These studies have begun to establish an exciting path that future studies can follow. Future work
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will help clarify which of the many imaging methods available at hand will be most beneficial in which clinical situations, and we look forward to those results.
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