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New MRI Protocol Refines CAD Risk Assessment - full text pdf publication attached
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MedPage Today
Published: July 12, 2011
"In this study, the plasma levels of hsCRP were significantly higher in the HIP group compared with the non-HIP group, and increased levels of hsCRP were independently associated with the presence of HIP. Increased hsCRP levels are an independent predictor of cardiovascular disease (33), and our results suggest that the presence of both MPRAGE-detected HIP and elevated hsCRP levels may indicate the presence of both vulnerable and inflammatory activated plaques."
"no studies have evaluated the relationship between carotid artery plaque vulnerability detected by MRI and subsequent coronary events. In the present study, we hypothesized that the presence of carotid high-intensity plaques (HIP) visualized by MPRAGE predicted future coronary events in patients with clinically stable CAD."
"A univariate analysis of coronary risk factors, carotid ultrasound data, and MRI analysis demonstrated that maximum IMT, high-intensity plaque, multivessel CAD, high-sensitivity C-reactive protein (hsCRP) and prior MI were all significant predictors of clinical coronary events"
"The presence of HIP detected by MPRAGE in the carotid arteries predicts the development of future coronary complications in patients with stable CAD. Noninvasive evaluation of carotid plaques using MRI with MPRAGE is clinically informative in the risk stratification of CAD patients."
An MRI protocol for carotid plaque delivered a more clinically relevant risk assessment for coronary artery disease than conventional measurements of intima media thickness (IMT), according to a new study.
Using this protocol, Teruo Noguchi, MD, of the National Cerebral and Cardiovascular Center in Suita, Japan, and colleagues identified the presence of high-intensity plaque as the strongest independent predictor of cardiac events, with a hazard ratio of 3.15 (95% CI 1.93 to 4.48, P<0.0001).
For this study, reported in the July issue of the Journal of the American College of Cardiology, Noguchi's group used magnetization-prepared rapid acquisition with gradient echo (MPRAGE) MRI to observe high-intensity signals in carotid plaques to determine if the presence of these signals was associated with cardiac events.
Action Points
· Explain that a new method of assessing carotid plaque using a special MRI technique was found to be superior to intima media thickness in predicting coronary events in patients with known coronary artery disease.
· Note, though, that the number of patients and the number of composite coronary events was low.
They looked at the signal intensity of carotid plaques in 217 patients with clinically stable coronary artery disease (CAD) using the MPRAGE MRI technique.
They defined stable CAD as the absence of episodes of angina at rest on admission in patients with angiographically documented stenosis of greater than 50% in at least one of the major coronary arteries.
IMT measurement was conducted for all patients via ultrasonography with a 7.5 MHz linear-array transducer prior to MR imaging on a 1.5-tesla unit with standard neck and spine array coils.
The MPRAGE protocol is a noncontrast, T1-weighted, inversion recovery-based 3-D imaging technique. Gadolinium-enhanced, multislab, 3-D time-of-flight MR angiography also was performed to determine lumen shape and plaque morphology after MPRAGE imaging.
Using a 5-8 mm region of interest, a radiologist analyzed the carotid plaque signal intensity on the MPRAGE images relative to that of the adjacent muscle.
Patients with plaques in either the right or left carotid artery in which any region of the plaque exhibited a signal intensity 200% greater than the adjacent muscle were placed in the high-intensity plaque group (116 patients). The remaining 101 patients were placed in a non-high-intensity plaque group.
The high-intensity plaque group also had lower HDL cholesterol levels, more multivessel coronary artery disease, a greater history of previous MI, higher high-sensitivity C-reactive protein, and increased IMT values.
After imaging was completed, all patients were followed up at the facility for a period of 12 to 72 months, or until the occurrence of clinical coronary events including cardiac death, nonfatal acute MI, unstable angina, or unplanned hospitalization for recurrent angina. These events were grouped together as a composite outcome.
The mean follow-up time was 38.3 months. During that period, there were 31 coronary events in the high-intensity plaque group, but only five in the non-high-intensity plaque group.
Unstable angina accounted for 16 of the 31 events in the high-intensity plaque group and was the only one by itself that was statistically significant.
"The presence of high-intensity plaque was significantly associated with an increased probability of coronary events in patients with stable CAD (P<0.001 by log-rank test)," the authors wrote.
A univariate analysis of coronary risk factors, carotid ultrasound data, and MRI analysis demonstrated that maximum IMT, high-intensity plaque, multivessel CAD, high-sensitivity C-reactive protein (hsCRP) and prior MI were all significant predictors of clinical coronary events (P<0.05), according to the researchers.
Further analysis determined that the presence of high-intensity plaque "was found to be the most significant independent predictor of future coronary complications in patients with stable CAD compared with IMT (HR 1.62, 95% CI 0.97 to 2.44, P=0.055), hsCRP, previous MI, and multivessel CAD," the authors stated.
Limitations of the study included a relatively small number of patients and the fact that few patients experienced one of the primary endpoints during the study, which meant the study did not have sufficient statistical power to ascertain whether or not the new marker was superior to established risk factors, according to the investigators.
Although these results are "exciting and promising," translation of the main findings to a more general high-risk population will be challenging, wrote Chun Yuan, PhD, of the University of Washington School of Medicine in Seattle, and colleagues in an accompanying commentary.
"Prospective, serial studies with MRI will result in a better understanding of the nature and etiology of intraplaque hemorrhage, may lead to the discovery of novel therapies to prevent its development, and will be needed to assess whether such therapies lead to a reduction in coronary and carotid events," they wrote.
The other commentary authors reported no relevant disclosures.
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J Am Coll Cardiol, 2011; 58:416-422
High-Intensity Signals in Carotid Plaques on T1-Weighted Magnetic Resonance Imaging Predict Coronary Events in Patients With Coronary Artery Disease - pdf attached
"Conclusion: The presence of HIP (high intensity plaque) detected by MPRAGE in the carotid arteries predicts the development of future coronary complications in patients with stable CAD.
Noninvasive evaluation of carotid plaques using MRI with MPRAGE is clinically informative in the risk stratification of CAD patients."
Teruo Noguchi, MD*,*, Naoaki Yamada, MD, Masahiro Higashi, MD, Yoichi Goto, MD* and Hiroaki Naito, MD
* Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan
Department of Radiology, National Cerebral and Cardiovascular Center, Suita, Japan
ABSTRACT
Objectives: The purpose of this study was to determine whether high-intensity carotid plaques visualized by a noncontrast T1-weighted imaging technique, magnetization-prepared rapid acquisition with gradient echo (MPRAGE), predict future coronary events in patients with clinically stable coronary artery disease (CAD).
Background: Coronary plaque vulnerability to rupture can be assessed by examining for the presence of atherosclerosis and measuring intima media thickness (IMT) in surrogate vessels such as the carotid arteries. We previously showed that MPRAGE successfully identifies vulnerable carotid plaques as high-intensity signals. It remains unclear, however, if the presence of carotid high-intensity plaques (HIP) is associated with an increased risk of coronary events.
Methods: We examined the signal intensity of carotid plaques in 217 patients with clinically stable CAD using MPRAGE with magnetic resonance imaging and measured IMT with ultrasonography. A carotid HIP was defined as a signal >200% that of the adjacent muscle. All patients were divided into 2 groups according to the presence or absence of HIP, namely, the HIP group (n = 116) and the non-HIP group (n = 101), and were followed up for as long as 72 months.
Results: The presence of HIP was significantly associated with cardiac events compared to the non-HIP group (log-rank p < 0.0001). Furthermore, multivariate Cox regression analysis identified the presence of HIP as the strongest independent predictor of cardiac events (hazard ratio: 3.15; 95% confidence interval: 1.93 to 5.58, p < 0.0001) compared with IMT (hazard ratio: 1.62, 95% confidence interval: 0.97 to 2.44, p = 0.055) and other coronary risk factors.
Conclusions: Characterization of carotid plaques using magnetic resonance imaging with MPRAGE provides more clinically relevant information for the risk assessment of CAD patients than IMT.
Abbreviations and Acronyms AMI = acute myocardial infarction CAD = coronary artery disease CI = confidence interval HIP = high-intensity plaque HR = hazard ratio hsCRP = high-sensitivity C-reactive protein IMT = intima media thickness MPRAGE = magnetization-prepared rapid acquisition with gradient echo MRA = magnetic resonance angiography MRI = magnetic resonance imaging TE = echo time TR = repetition time
Rupture of vulnerable atherosclerotic plaques in the coronary vessels leads to acute coronary syndromes. Collectively, recent studies suggest that, rather than simply being a local vascular incident, plaque instability is a systemic problem present in multiple vascular beds throughout the body. Thus, it may be possible to assess the vulnerability of coronary artery plaques to rupture and the development of acute coronary syndromes by evaluating the stability and composition of plaques in other vessels (1-3). However, this has not been clearly established, and prospectively identifying a high-risk coronary artery disease (CAD) population vulnerable to plaque rupture remains difficult.
Magnetic resonance imaging (MRI) can be used to noninvasively assess carotid plaque characteristics in vivo. High-intensity signals observed in carotid plaques using inversion recovery-based 3-dimensional T1-weighted imaging-alternatively known as magnetization-prepared rapid acquisition with gradient echo (MPRAGE) (4) or magnetic resonance direct thrombus imaging (MRDTI) (5,6)-are associated with recent ischemic cerebrovascular events (6-8) and are related to complex plaques (type VI as proposed by the American Heart Association) (9,10). Several groups have used high-resolution multicontrast MRI to examine the relationship between plaque composition and cerebrovascular events, and their data suggest that MRI can successfully identify vulnerable carotid plaques (11-14). However, no studies have evaluated the relationship between carotid artery plaque vulnerability detected by MRI and subsequent coronary events. In the present study, we hypothesized that the presence of carotid high-intensity plaques (HIP) visualized by MPRAGE predicted future coronary events in patients with clinically stable CAD.
RESULTS
Baseline clinical characteristics. The baseline clinical characteristics of the study patients are shown in Table 1. The median, first quartile, and third quartile range of carotid plaque signal intensity relative to the adjacent muscle was 3.10, 2.67, 3.63, respectively, in the HIP group; and 1.51, 1.39, 1.70, respectively, in the non-HIP group. The HIP group had significantly higher levels of hsCRP and low-density lipoprotein cholesterol, higher rates of multivessel CAD and previous MI, lower levels of high-density lipoprotein cholesterol, and increased IMTmax values. There was no significant difference in the degree of carotid artery stenosis between the 2 groups, and there were no differences in the administered medications between the 2 groups.
MRI of carotid artery and prognostic value of HIP in stable CAD patients. One hundred sixteen of the 217 patients were categorized to the HIP group. Figure 1 shows representative MR images of patients in the HIP group (Figs. 1A and 1B) and non-HIP group (Figs. 1D and 1E). Patients were followed up for a mean of 38.3 months. There were 31 coronary events in the HIP group during the follow-up period, but there were only 5 such events in the non-HIP group (n = 101; p < 0.001) (Table 2). When these data were subjected to Kaplan-Meier analysis, the presence of HIP was significantly associated with an increased probability of coronary events in patients with stable CAD (p < 0.001 by log-rank test) (Fig. 2). Univariate analysis of coronary risk factors, carotid ultrasound data, and MRI analysis showed that IMTmax, HIP, multivessel CAD, hsCRP, and previous MI were all significant predictors of clinical coronary events (p < 0.05) (Table 3). When these factors were further analyzed by a multivariate Cox regression analysis, the presence of HIP was found to be the most significant independent predictor of future coronary complications in patients with stable CAD (hazard ratio [HR]: 3.15, 95% confidence interval [CI]: 1.93 to 5.58, p < 0.0001) compared with IMT (HR: 1.62, 95% CI: 0.97 to 2.44, p = 0.055) , hsCRP, previous MI, and multivessel CAD (Table 4). To further compare the presence of HIP to IMT, we used a cutoff value of >2.78 mm (i.e., the third quartile of IMT in the present study) to define elevated IMT and performed an alternative multivariate Cox regression analysis. When this cutoff value was used, IMT was significantly associated with cardiac events (HR: 1.79, 95% CI: 1.19 to 4.01, p = 0.021), but the presence of carotid HIP (HR: 3.10, 95% CI: 1.79 to 5.01, p < 0.0001) remained the strongest indicator of future coronary events.
DISCUSSION
We wished to identify a technique to allow for the better stratification of patients at risk of coronary events, and we hypothesized that the nature of atherosclerotic plaques throughout the vasculature could be associated with coronary plaque instability. As such, we used MPRAGE to examine the intensity of atherosclerotic plaques in the carotid arteries and followed up patients with both high- and low-intensity plaques for the subsequent development of coronary events. Our data suggest that the presence of HIP visualized by MPRAGE is a significant and independent predictor of future coronary events in patients with stable CAD. Furthermore, the presence of HIP was a stronger predictor of coronary events than increased carotid artery IMT. Thus, characterization of carotid plaques by MRI is clinically informative for risk stratification of patients with CAD.
Plaque instability and rupture were previously thought to be isolated events at a specific site within the vasculature, but recent observations suggest that plaque destabilization is a characteristic of some patients that occurs at multiple sites throughout systemic vascular beds (17,18). Thus, the presence of vulnerable carotid plaques may reflect a systemic problem with plaques within the coronary vasculature equally at risk to rupture and associated infarction. B-mode ultrasound of the carotid arteries can identify plaques and measure IMT, and both have been used as surrogate markers for cardiovascular disease. Although IMT and the presence of carotid plaques are highly related (19), the overall plaque area was a stronger predictor of future coronary events than IMT (20).
Additionally, carotid plaque characteristics, for example, echolucency, predicted coronary plaque complexity, and the development of coronary complications in patients with CAD (2,21). While current data indicate that other radiologic measures may be better than IMT for coronary risk stratification, we elected to use IMT in this study because IMT is a more established technique, more widely available, and better validated in large populations (22).
In the present study, we used the MRI modality MPRAGE to characterize carotid plaques in patients with stable CAD. MPRAGE is a T1-weighted technique that highlights intraplaque components with short T1 signal with high signal intensity. It is thought that the lipid-rich necrotic cores of vulnerable plaques give rise to the observed short T1 signal (14,23-25). Alternatively, this may arise from intraplaque hemorrhage and thrombus formation (9,14,26,27). The presence of high-intensity signals suggestive of complicated plaques was associated with subsequent ischemic cerebrovascular events, and this was recognized as an indicator of vulnerable carotid plaques (8,9). However, our current data greatly expand the significance of carotid HIP by showing that carotid HIP is a significant and independent predictor of future coronary events in patients with stable CAD. In fact, the presence of carotid HIP is a stronger indicator of future coronary events than increased IMT.
Recent advances in technology have allowed for the development of techniques that allow for the direct examination of coronary artery plaque composition, for example, intravascular ultrasound and angioscopy. However, these techniques are invasive and are not practical for use in routine screening for the management and risk assessment of patients with CAD. Therefore, noninvasive imaging modalities capable of identifying patients harboring unstable coronary lesions are needed. Hence, the MRI-based evaluation of carotid plaques described here provides clinically important information on the vulnerability of coronary atherosclerotic plaques to rupture and correlates with future clinical outcome.
Inflammation plays important roles in atherogenesis and plaque rupture (15,28-31). A common inflammatory pathway linking carotid and coronary artery plaque activation has been proposed based on the observed high C-reactive protein levels seen in patients with CAD and echolucent carotid plaques (32). In this study, the plasma levels of hsCRP were significantly higher in the HIP group compared with the non-HIP group, and increased levels of hsCRP were independently associated with the presence of HIP. Increased hsCRP levels are an independent predictor of cardiovascular disease (33), and our results suggest that the presence of both MPRAGE-detected HIP and elevated hsCRP levels may indicate the presence of both vulnerable and inflammatory activated plaques.
Study limitations. This study was limited by the relatively small number of patients examined, and a few patients experienced a primary endpoint during the study. Hlatky et al. (34) reported that a greater number of outcome events are needed to provide adequate statistical power to fully evaluate whether a novel risk marker contributes additional prognostic information to an established set of risk factors in a multivariable model rather than simply indicating whether the new marker is a prognostic tool by itself. Therefore, while our data show that the presence of HIP is a risk factor for coronary events, the relative importance of HIP compared to other cardiac risk factors should be evaluated and confirmed in a larger prospective study. We enrolled patients with stable CAD with >50% stenosis, and most acute coronary events occur with low-grade or mild coronary stenosis. Additionally, we did not use a multicontrast approach including 3 basic contrast weightings (T1W, proton density, T2W). Use of these multicontrast approaches in conjunction with time-of-flight MRA has been shown to provide information regarding the thickness of the fibrous cap, the lipid-rich necrotic core, and intraplaque hemorrhage (12,35-37). The combination of MPRAGE with proton density and T2W techniques could further enhance imaging based predictions of coronary plaque vulnerability.
The risks of nephrogenic systemic fibrosis were less clearly understood during the study period in 2002 to 2005, and we did not exclude patients with a glomerular filtration rate <45 ml/min/1.73 m2. The overall mean glomerular filtration rate of the study population was 78 ± 19 ml/min/1.73 m2, and only 6 (2.7%) of the 217 patients had a GFR <45 ml/min/1.73 m2. None of these patients had nephrogenic systemic fibrosis after administration of gadolinium.
Additionally, although we excluded 9 patients who had cardiac events in the first year of follow-up, the inclusion of these patients in the analyses did not affect the study results (data not shown). Finally, the number of clinical events in the study group was small, and follow-up was limited to 3 years. A more substantial, longer-term study with more patients is needed to clarify the short- and long-term prognostic roles of MRI as well as the role of MRI screening for high-risk asymptomatic patients.
Conclusion
The presence of HIP (high intensity plaque) detected by MPRAGE in the carotid arteries predicts the development of future coronary complications in patients with stable CAD.
Noninvasive evaluation of carotid plaques using MRI with MPRAGE is clinically informative in the risk stratification of CAD patients.
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EDITORIAL
What Will Noninvasive Carotid Atherosclerosis Imaging Show Us About High-Risk Coronary Plaques?*
Chun Yuan, PhD,*, Nayak L. Polissar, PhD and Thomas S. Hatsukami, MD
Department of Radiology, University of Washington School of Medicine, Seattle, Washington
The Mountain-Whisper-Light Statistical Consulting, Seattle, Washington
Department of Surgery, University of Washington School of Medicine, Seattle, Washington
With the advent of many noninvasive imaging techniques to characterize atherosclerotic plaques in vivo, it is time to investigate the relationships of high-risk lesions in different vascular beds as a systemic disease.
The quest to noninvasively identify vulnerable atherosclerotic plaques that pose an increased risk of heart attack and stroke may have gained another tool in magnetic resonance imaging (MRI). Vulnerable plaque imaging remains a challenging field for many reasons: from the spatial resolution needed to identify thin cap fibroatheroma in the coronary arteries, to quantifying the amount of lipid content and inflammation in plaques (1). The technical challenges are further compounded by there perhaps being multiple vulnerable plaques in a single vascular bed (i.e., coronary arteries), and as a systemic disease, atherosclerosis may develop in multiple vascular beds (2). Direct noninvasive coronary vulnerable plaque imaging (with computed tomography) remains limited to the examination of calcium deposits and categorization of lesions as hard versus soft plaque rather than a direct characterization of thin cap fibroatheroma or other high-risk features (3). In this issue of the Journal, Noguchi et al. (4) suggest a direct plaque imaging approach to predict risk of future cardiovascular events. In this case, the direct plaque imaging technique is focused on bright T1 signals in MRI of the carotid arteries. The authors demonstrate that these "high-risk" signals in the carotids can help predict coronary events.
With a larger size, easy access by many imaging techniques, and less motion compared to the coronary arteries, it is natural that carotid artery atherosclerosis be considered as a surrogate for coronary artery disease. In particular, increased carotid intima media thickness (IMT) has been shown to be associated with increased risk of cardiovascular disease events (5), although the nature of this association is controversial. Carotid IMT, obtained from B-mode ultrasound, is not a direct measure of carotid plaque, and a recent summary of meta-analyses concludes that regression or slowed progression of carotid IMT does not reflect reduction in cardiovascular events (6). The true value of using the carotid artery as a surrogate of coronary artery disease may lie in linking the specific high-risk atherosclerotic lesions or lesion features in the 2 vascular beds. Indeed, in a large study of the histological features of plaques obtained from patients undergoing carotid endarterectomy, Hellings et al. (7) showed that presence of carotid plaque hemorrhage or marked intraplaque vessel formation predicted an increased risk for composite events (vascular death, nonfatal stroke, nonfatal myocardial infarction) during follow-up. While this study provides compelling evidence of a possible linkage between "high-risk" plaque features across vascular beds in patients requiring carotid surgery, the findings by Noguchi et al. (4) suggest that this association holds true among those with earlier stage, asymptomatic carotid atherosclerosis.
The bright T1 signal in MRI reported in this study is believed to be from intraplaque hemorrhage (IPH) and likely due to the degradation of hemorrhage into methemoglobin. Methemoglobin shortens the longitudinal relaxation time (T1) and gives the bright signals in T1-weighted images such as in the magnetization-prepared rapid acquisition gradient echo (MPRAGE) and time-of-flight and fast spin echo techniques. Each of these sequences has been validated with histology to detect IPH in the carotid atherosclerosis (8-13). More importantly, a series of prospective and cross-sectional studies have found a clear link between IPH and accelerated progression in carotid plaque burden, as well as associations between carotid IPH and the development of future ischemic neurological events (14-18).
The MRI studies of persons with asymptomatic, minimal carotid stenosis have demonstrated a surprisingly high prevalence of carotid plaques with IPH (19,20) and highlight the limitation of stenotic severity as the principal criterion for disease assessment. In the cohort reported by Noguchi et al. (4), >50% of the carotid plaques had MRI evidence of IPH, yet they had a mean stenosis of only 22.5%. Recently, a carotid atherosclerosis scoring system was introduced by Underhill et al. (21) to predict the presence of carotid IPH, and indicated that plaque burden and the size of plaque features such as the lipid-rich necrotic core were more strongly associated with IPH presence than with the severity of luminal narrowing.
The work of Noguchi et al. (4) is exciting and promising, but there are also several limitations associated with this study. Given the prominent role that high-intensity plaques (HIP) play in their report, there is no analysis with a continuous formulation of HIP that, in theory, reflects the size of intraplaque hemorrhage of a plaque and may enhance the statistical power of the study. It would also be useful to see if there is a dose-response relationship between continuous HIP and the risk of an event. Likewise, the reliability and robustness of HIP detection for general clinical application needs to be assessed.
The subjects selected for this study had confirmed carotid atherosclerosis and stable coronary artery disease. Translation of the main findings from this study to a more general high-risk population will be challenging. Interestingly, a recent MRI-based study (22) found that among subjects with confirmed CAD, only 9.7% had carotid plaques with intraplaque hemorrhage. It is clear that all these subjects belong to the high-risk population, but whether there is a better tailored diagnosis and treatment for a subset within this population remains to be seen.
Another observation from the study is the very abrupt decrease in risk of an event in the HIP group at about 18 to 20 months, with the curve leveling off considerably and a much weaker (and perhaps nonexistent) leveling off in the non-HIP group a little later (Fig. 2). That seems to suggest a statistically significant and approximately eightfold decrease in risk of an event per unit time comparing months 0 to 20 to months 20 to 40. That clearly needs further study and explanation.
Future Work
The paper by Noguchi et al. (4) provides a strong start in the effort to test the hypothesis that high-risk plaque features are expressed systemically. Larger, multicenter studies are needed to confirm these promising initial findings. A key question is how plaque imaging should alter patient management. Ongoing studies such as the High-Risk Plaque Initiative (23) will provide valuable insight toward identifying persons who by current clinical guidelines are considered low to intermediate risk, and as such are currently not aggressively managed, and who may benefit from MRI plaque imaging.
Finally, what is even more exciting is that the study has been conducted through noninvasive imaging, and thus offers the potential to examine the changes in these lesions over time. Prospective, serial studies with MRI will result in a better understanding of the nature and etiology of IPH, may lead to the discovery of novel therapies to prevent its development, and will be needed to assess whether such therapies lead to a reduction in coronary and carotid events.
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