Discrete coronary lesions, both total and subtotal occlusions, may appear as either areas of signal void, decreased flow signal, or vessel wall irregularity. It is thus very important to be aware of these important differences between coronary MRA and MRA of large vessels elsewhere in the body. Also, because of collateral flow, a total occlusion may have slow-moving fluid present in the vessel distal to the occlusion and show a normal vessel signal.
Diffusely diseased coronary arteries cannot be distinguished from small-caliber normal vessels by coronary MRA. A dominant left coronary system with a small-caliber RCA can simulate diffuse disease in the RCA, and vice versa. Women with small-caliber coronary vessels are also more difficult to study with coronary MRA.
PIONEERING WORK WITH FIRST-GENERATION CORONARY MR ANGIOGRAPHY: THE 1993–94 PERIOD.
A historical review of the initial reports on the use of coronary MRA for coronary artery lesion detection can be very educational. It illustrates a typical cycle: the initial enthusiasm of the first very positive and promising preclinical reports and then the more negative follow-up reports when other investigators try to duplicate the initial work. This seems to be a very typical scenario in the early stages of new imaging technology implementations in medicine. Similar scenarios can be found in other areas of thoracic imaging, such as the use of computed tomography (CT) for pulmonary embolism detection and the use of electron beam CT (EB-CT) for three-dimensional (3D) coronary artery visualization.
WORK BY MANNING ET AL., REPORTED IN 1993
Initial clinical testing of the first-generation coronary MRA technique was performed at the Beth Israel Hospital in Boston and reported in the March 1993 issue of the New England Journal of Medicine. In this historical article, Manning et al. reported for the first time on the ability to detect coronary occlusion and stenosis by using MRA in a series of 39 patients referred for elective coronary angiography. This paper brought hope to the field of cardiology and medicine that a noninvasive coronary imaging technique soon would become available. It created great interest by industry and MRA vendors for this new and extremely promising application of cardiac MRA. More than anything else, it helped increase the research efforts in new uses of cardiac MRA techniques. The national and international press got involved, and this report went beyond just the medical media.
In this first clinical study, coronary MRA, as compared with conventional angiography, had 90% sensitivity and 92% specificity for correctly identifying individual vessels with 50% or greater angiographic stenoses. The corresponding positive and negative predictive values were 0.85 and 0.95, respectively. The overall sensitivity and specificity for correctly classifying individual patients as having or not having serious coronary disease were 97% and 70%, respectively, with corresponding positive and negative predictive value of 0.90 and 0.88, respectively. Lesion detection was highest in the left main coronary artery. Coronary MRA showed the lowest sensitivity for lesion detection in left circumflex artery (71%) and the lowest specificity in the right coronary (78%). In a follow-up study of 72 patients with 81 significant lesions in a total of 271 visualized coronary arteries (and 39% of patient without significant lesions), the sensitivity for an individual vessel with stenosis remained 90%.
WORK BY DUERINCKX ET AL., REPORTED IN 1994
Subsequent attempts by other investigators to reproduce these results based on blinded studies have not been as successful. Duerinckx et al. were the first to report in December 1993 that the 90% sensitivity for lesion detection by using first-generation coronary MRA was optimistic and could not be reproduced in a double-blinded prospective study. Their study was published in the December 1994 issue of Radiology. The publication of the article by Duerinckx et al. confirmed what several other investigators and industry people were starting to discover and had to admit; that although very promising, and in some patients spectacular, the images routinely produced with first-generation coronary MRA were not consistent enough to reproduce the results first reported by Manning et al. This paper has historical importance, because it set a more realistic tone for what first-generation coronary MRA can accomplish.
As can be expected, great controversy erupted over these discrepancies in the performance of first-generation coronary MRA techniques. The original correspondence between Manning and Duerinckx was published in the June 1995 issue of Radiology. Duerinckx et al. were not alone in disagreeing with Manning et al. Indeed, from 1994 to 1995, the reported sensitivity for detection of significant (≥50%) lesions was highly variable: 36% in an initial study by Post et al. of 14 patients with 14 significant lesions; 33% to 75% in a follow-up study by Post et al. of 35 patients with 35 stenoses; 63% average sensitivity (range, 0%–75%) in a study by Duerinckx et al. of 20 patients with 27 proximal lesions; 65% in an initial study by Pennell et al. of 17 patients with 23 lesions; 88% in a follow-up study by Pennell et al., using a nonblinded analysis of 31 patients with 41 lesions; 83% to 100% in a study by Nitatori et al. in 50 patients; and 56% in a study by Mohiaddin et al. in 16 heart transplant patients with nine lesions.
WHY THE DISCREPANCY IN RESULTS BETWEEN MANNING AND DUERINCKX?
The failure of other investigators to achieve a 90% sensitivity and 92% specificity for coronary lesion detection was not caused by differences in techniques relating to relative poor temporal resolution, shorter echo times, or worse patient cooperation, unlike some statements to the contrary. In fact, both Manning and Duerinckx used the same MR pulse sequences designed and provided by the same company (Siemens Medical Systems, Inc, NJ). Both investigators took great care in patient preparation and prescan breath-hold practice. In retrospect, the discrepancy in results can most likely be explained by interobserver differences in interpretation of a similar set of MR images. The most important difference between the Manning and Duerinckx studies may well be the “human factor,” that is, the level of confidence chosen by each investigator to call an anomaly on an MR image of a lesion.
An important practical problem with first-generation 2D coronary MRA is the potential for overreading or underreading of coronary lesions. Because only one slice is viewed at a time, and spatial registration between slices in never guaranteed, it can be difficult to distinguish between an apparent lesion caused by an out-of-plane vessel course and a true lesion. This is compounded by the limited spatial and temporal resolution (typically 1 mm in-plane spatial and 80 to 100 ms temporal resolution). It is important for users of this technique to understand these interpretative difficulties. With second-and third-generation coronary MRA techniques, many of these problems disappear. One has to adhere to strict radiologic interpretation criteria or else one would have false-positive readings in almost 100% of normal patients.
Several explanations are possible for misinterpretation of a coronary lesion on 2D coronary MRA. These include spatial and temporal resolution, timing of the acquisition (within the cardiac cycle), irregular breathing and misregistration between breath-holds, partial volume averaging of tortuous vessels and overlapping adjacent anatomic structures, reverse flow past an area of stenosis caused by collateral flow, and the unknown signal and contrast characteristics of vessel wall and plaque on coronary MRA sequences.
LESION DETECTION USING FIRST-, SECOND-, AND THIRD-GENERATION CORONARY MRA: THE 1995–2000 PERIOD
It was originally hoped that coronary MRA could become a noninvasive screening tool for the detection of coronary artery lesions. The results with first-generation coronary MRA in the 1993–1994 period were very promising but somewhat variable. The first-generation 2-D breath-hold MR imaging technique was tested by several investigators on a total of approximately 224 patients and was able to detect significant coronary artery lesions (greater than 50% diameter narrowing) with a sensitivity ranging from 33% to 100% (see Table 2, top). The reported sensitivity also varied depending on the vessel examined. Because all the early studies were done with a surface coil positioned on the anterior chest wall, the more posteriorly located circumflex coronary artery was the more difficult vessel to visualize. More recent studies have used phased-array thoracic coils, with better visualization of the circumflex coronary artery. The early 3D techniques did not make a significant difference. The initial clinical results were very disappointing, with a sensitivity of 0% to 38%, as shown in Table 2. Then in 1994 to 1995, second-generation 3D coronary MRA trials were performed, using navigator-pulse feedback. With the original implementation of these techniques, a few investigators were able to show a sensitivity of 65% to 87% for lesion detection, as shown in Table 2. Many modifications and improvements for this second-generation coronary MRA approach have been proposed and implemented. These improved second-generation coronary MRA techniques show great promise. However, even these improved navigator techniques still require long acquisition times, with all the inherent risks of erratic breathing or motion. Thus, there is interest in developing newer techniques, referred to as the third-generation coronary MRA, that allow multiple slice acquisition in a single breath-hold. Only very preliminary clinical results are available for the third-generation coronary MRA techniques.
The results of all the preclinical trials of coronary MRA for coronary artery lesion detection are summarized in Table 2. After 7 years of preclinical trials using many different coronary MRA techniques, no technique has yet emerged as superior and can provide a sensitivity and specificity for coronary lesion detection that compares with traditional contrast coronary angiography.
The performance of first-generation coronary MRA is still relatively time-consuming and requires the presence of a trained cardiac imager. With a moderate amount of training and practice, most radiologists and cardiologists should be able to perform these studies. Several excellent review articles have provided guidance for the time-efficient performance of these examinations.
UNRESOLVED ISSUE: WILL THE SENSITIVITY FOR LESION DETECTION BE GOOD ENOUGH FOR CLINICAL PRACTICE?
The most important limitation to the clinical implementation of coronary MRA is the great variation in the appearance of significant (≥50%) coronary lesions and the large number of image artifacts that can be misinterpreted as representing lesions. Although this has been best documented for first-generation 2D coronary MRA techniques, preliminary evidence in normals seems to indicate that the problem may be worse with the initial implementations of the second-generation techniques by use of navigator pulses. In a study of normal volunteers imaged with a 3D coronary MRA technique and retrospectively gated navigator feedback, Stehling found that approximately 50% of the examinations were of unacceptable quality, making interpretation of the images difficult or impossible. Nevertheless, several investigators, using this early implementation of the navigator technique (and using the same MR scanner and software from the same vendor), reported much better results in patients.
It is obvious that the coronary MRA techniques available today have limitations when it comes to lesion detection. Clinical studies are needed to determine whether these techniques, with their limitations, would still have an impact on selecting clinical pathways for patient care and intervention. The ultimate clinical utility of a coronary MRA screening technique should be compared with other noninvasive alternatives such as coronary calcium screening by using EB-CT, EB-CT visualization of the coronary vessels, echocardiography, nuclear medicine studies, and even treadmill stress testing. None of the existing noninvasive techniques have a 100% sensitivity. Each technique has its own limitations, and the ultimate relative value of coronary MRA with respect to these techniques remains to be determined in future studies.
Another problem is that the expectations for coronary MRA were somewhat unrealistic to begin with. MRA in peripheral vessels and even in larger vessels such as the carotid arteries has well-known limitations and image artifacts. Nevertheless, MRA of the carotid arteries is well accepted and clinically used. Expecting that MR techniques applied to the small vessels on the heart that are subject to cardiac and respiratory motion would be able to perform better than in relatively stationary vessels such as the peripheral vasculature or the carotid arteries was perhaps unrealistic. In addition, one expects a very high sensitivity for lesion detection in the coronary territory, whereas a lesser sensitivity in the peripheral vasculature would be acceptable.
Lesion appearance and the presence of collateral flow also complicate image interpretation, as described earlier. Discrete coronary lesions (total and subtotal occlusions) may appear as areas of signal void, decreased flow signal, or vessel wall irregularity. A subacute thrombus can mimic flowing blood. This is sometimes different from the more traditional appearance of lesions in larger vessels, as seen on MRA. Also, because of collateral flow, a total occlusion may have slow-moving fluid present in a vessel distal to the occlusion and show a normal vessel flow signal. A correlate of this is the fact that the significance of a coronary lesion cannot be quantitated on coronary MRA. The typical spatial resolution is 1.5 × 1 × 4 mm for coronary vessels measuring 2 to 4 mm in diameter. The problems with measuring luminal diameter narrowing on coronary MRA have been clearly outlined in two recent studies. Pennell et al. classified the degree of MR signal loss in the region of a known coronary artery lesion as severe or partial and in addition noted when an irregular vessel outline was present. The main percentage of stenosis was significantly different for each type of signal loss, suggesting that visual assessment of signal loss can be a qualitative guide to stenotic severity. They also measured directly on the viewing screen the relation between the proportion of magnetic resonance signal loss at the site of stenosis and compared this with the diameter of the stenosis as assessed by conventional angiography. They found that there was a significant relationship between stenosis severity and magnetic resonance signal loss, although with a considerable scatter in individual measurements. They were never able to measure “luminal diameter reduction.” Shimamoto et al. provided a detailed analysis of the use of spatial profile curves to better measure the diameter of coronary arteries on MRA. This problem in quantitating the severity of stenosis was discussed early on by Duerinckx and Urman and Pennell et al.. Duerinckx et al., have suggested that the problem in quantitating the severity of stenosis can be circumvented by using “confidence levels” for the presence of significant disease and by using receiver operating curve (ROC) analysis to interpret image data.
IS THERE A GOLD STANDARD TO EVALUATE NEW TECHNOLOGIES?
A detailed protocol for the interpretation and reading of coronary MRA has been described by Duerinckx et al.. This protocol includes, for each segment of vessel (for the visualized portion of the coronary anatomy), the following: (1) length and width of vessel; (2) grading of image quality; and (3) likelihood of presence of significant lesion or any (mild or moderate) disease (i.e., confidence levels for ROC analysis). This protocol, together with an estimate of intraobserver and interobserver variability in interpretation, could form the basis for multicenter evaluations of any of these new coronary MRA techniques. However, this presumes the existence of a “gold standard” to assess the MRA findings. Does such a standard really exist? We discuss the problems with the generally accepted standard of iodinated contrast–based angiography.
The presence or absence of coronary artery lesions is traditionally evaluated with coronary angiography. However, great interobserver variability in the interpretation of coronary angiograms has been well documented. Moreover, the assessment of significance of coronary stenosis based on interpretation of the coronary angiogram only is questionable. We briefly address both of these issues.
One older study by Zir et al. from 1976 showed that in only 65% of coronary angiograms did four observers agree about the significance of a stenosis (defined as greater than 50% of luminal narrowing) in the proximal or mid-left anterior descending coronary artery. In this study, four experienced coronary angiographers (two radiologists and two cardiologists) independently assessed the location and degree of coronary artery stenosis in 20 coronary angiograms and showed a substantial degree of variability in the interpretation of coronary angiography. This was even more surprising in the sense that all four angiographers were from the same institutions and had frequently participated as a group in the interpretation of coronary angiograms. The 20 angiograms in their study included the typical spectrum of coronary angiographic findings with very few normal coronary arteries or cases with single-vessel disease.
The concept of what is a “gold” standard is constantly being reevaluated and questioned. The problems of interobserver variability are not unique to the interpretation of coronary angiograms but have also been reported in the interpretation of other vascular imaging studies. The reasons for the observed variability in coronary angiogram interpretation in the older studies such as that of Zir et al. can be related to several factors: a limited number of projections; partial visualization of the vessel segments with lesions; the quality of the coronary angiograms; and differences in perception. Some of these problems no longer exist with the newer cardiac cathetherization laboratories. However, many important problems remain. One of the most important factors contributing to the variability in interpretation was disagreement as to which portion of the vessel to use as a normal reference when calculating the percentage of coronary stenosis. Frequently large segments of the vessels are abnormal, making such determinations difficult. There may be vessel dilation, lesions may be multiple, or lesions may be smooth or tapering. Several approaches may reduce the error attributable to interobserver variability. One would be to combine independent readings. Another would be to use a consensus opinion based on joint reading of the coronary angiogram.
These difficulties in determining the level of stenosis of a coronary lesion could partially explain the problems with the poor correlation between coronary stenosis and functional significance of a coronary lesion. The variations in cross-sectional shape of the lesions also account for some of the discrepancies. This well-known phenomenon can be solved by obtaining multiple projections of single lesions. Unfortunately, in the case of a left main coronary artery or proximal left anterior descending coronary artery, often many overlapping vessels are difficult to separate even with several views.
One has to keep these discrepancies in coronary angiogram interpretation in mind when designing and interpreting studies comparing new technologies such as coronary MRA or EB-CT angiography with conventional coronary angiography. If one presumes that the conventional contrast-based coronary angiography is the gold standard, and does not take into account the great variability in interpretation, one may draw erroneous conclusions about the performance of either MR-or EB-CT–based coronary angiography. Thus, the results of prospective blind studies comparing both technologies should be interpreted with great caution. Each study should include a retrospective analysis of the data, because in some instances coronary MRA or EB-CT angiography may provide additional information that is difficult to gain from a traditional conventional coronary angiogram that provides a limited number of views of multiple superimposed vessels.
CORONARY LESION DETECTION BY MR IN THE FUTURE
Coronary MRA technique development has been proceeding at a very fast pace, indeed so fast that most techniques cannnot be evaluated by more than one or two investigators before everybody moves on to the next technique. Clinical users should not be disappointed by this or view this as an indication that these techniques are not working. First-generation coronary MRA techniques are more than adequate for a large number of specific clinical applications, and are even capable of detecting significant coronary lesions with a sensitivity of 65% to 80% in many centers. The early implementation of the second-generation coronary MRA techniques (using retrospective respiratory gating) required long acquisition times, which explains their unpredictable behavior. When images were good they were very good, but equally often they were very bad and uninterpretable. The improved second-generation coronary MRA techniques using navigator pulse feedback and adaptive prospective (or retrospective or interactive) correction of slice position or signal averaging dramatically improve the reliability and image quality and thus increase the sensitivity of the technique. The newer third-generation techniques appear very promising and easy to use. The advent of blood pool agents also will impact our capability to detect lesions. Hopefully, we will soon have a useful array of complementary noninvasive MRA approaches to the evaluation of coronary lesions that will be easy to use and will provide reproducible results.
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Editor: Jeffrey S. Klein
Associate Editors: Ann Leung, MD
David Lynch, MD, Jung-Gi Im, MD
Michio Kono, MD, Charles White, MD
Guest Editor: William Stanford, M.D.
Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
Magnetic resonance angiography; Coronary arteries; Coronary atherosclerosis