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Coronary Artery Disease: Combined Stress MR Imaging Protocol-One-Stop Evaluation of Myocardial Perfusion and Function¹

¹ From the Departments of Cardiology (P.R.S., D.d.B., N.J.S.) and Radiology (N.M.H., R.P.K., J.L.T.), Glenfield Hospital, Groby Rd, Leicester LE3 9QP, United Kingdom; and the Department of Radiology, University of Leicester, United Kingdom (A.J., B.M., G.R.C.). Received April 15, 1999; revision requested June 2; revision received July 9; accepted July 26. Supported in part by a grant from the Department of Research and Development, Glenfield Hospital, Leicester, UK. P.R.S. supported by a fellowship from the British Heart Foundation. Address correspondence to P.R.S. (e-mail: prsensky@innotts.co.uk).

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The authors developed and tested a dual stress magnetic resonance (MR) imaging protocol to evaluate myocardial perfusion, function, and hibernation. The technique was well tolerated, and high-quality images were achieved. The comprehensive information obtained can be used to guide clinical management decisions regarding coronary artery revascularization procedures. This protocol offers a one-stop assessment of patients with coronary artery disease with use of a clinical MR imager.

Index terms: Coronary vessels, MR, 51.121412, 51.121413, 54.12144 • Heart, function, 51.12144 • Heart, perfusion, 51.12144 • Myocardium, MR, 511.12144

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Complete assessment of a patient with coronary artery disease to evaluate suitability for a revascularization procedure such as coronary artery bypass grafting or percutaneous angioplasty should ideally be able to (a) determine the site of the disease and extent of any accompanying myocardial ischemia, (b) predict improvement in left ventricular (LV) function and long-term outcome, and (c) determine the patient risk for the procedure.

The presence of an epicardial artery stenosis can lead to impaired coronary blood flow and reduced myocardial perfusion. The myocardium supplied by the affected artery is placed at risk of ischemia and injury. The site and anatomic extent of the resultant myocardial perfusion deficit can identify myocardium at jeopardy (ie, the likely extent of damage from total artery occlusion) (1). The functional significance of any coronary artery lesion can be determined on the basis of the effect on myocardial blood flow at rest and during exercise or pharmacologically induced stress (2). Myocardial perfusion is currently investigated in the clinical setting by means of thallium scintigraphy, positron emission tomography (PET), or both. However, both these modalities have limited spatial resolution and involve the use of ionizing radiation.

Evaluation of resting LV function gives an estimate of preexisting myocardial damage and can be used to assess the patient's risk for any contemplated procedure (3). However, areas of the left ventricle that appear dysfunctional at rest may contain hibernating myocardium. Hibernating myocardium is a state of chronic LV contractile dysfunction (4) that is fully reversible with reperfusion. Its identification is important as, in comparison with scar tissue, hibernating myocardium demonstrates functional improvement after successful revascularization (5) and is associated with a lower surgical risk (6). A key diagnostic feature of hibernating myocardium is a recruitable contractile reserve after low-dose inotropic stimulation (7). Stress echocardiography is used clinically to assess contractile reserve, but it is both subject and operator dependent. Preserved cell metabolism and membrane integrity are also features of myocardial hibernation that can be identified with thallium 201 scintigraphy and PET (8,9).

Current magnetic resonance (MR) imaging techniques have the clinical potential to evaluate these parameters. Dynamic sequences, in association with paramagnetic contrast agents, allow first-pass myocardial perfusion studies to be performed (10). The addition of stress agents enables the evaluation of vasodilator-induced perfusion defects that may indicate a reduction in myocardial perfusion reserve (11,12). The high spatial resolution of MR imaging facilitates delineation of perfusion heterogeneity in the different myocardial layers. This can therefore provide detailed information regarding the extent and physiologic significance of coronary artery disease (13). Cine MR imaging permits the assessment of resting global and regional LV function and myocardial contractile response to inotropic stress (14,15). From this, information about the presence of scar tissue and hibernating myocardium can be deduced. Surgical risk can also be evaluated.

We have developed a comprehensive stress MR imaging protocol for use with clinical imagers that evaluates resting and stress perfusion, contractile reserve, and global LV function in a single 50-minute examination. We have designed a method to display the resultant data. This preliminary study was focused on the patient tolerance and diagnostic potential of this protocol.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patient Selection
After local ethics committee approval, six patients (five men and one woman; mean age, 57.9 years; age range, 49–64 years) with coronary artery disease at angiography were selected for study. The nature of the procedure was fully explained and informed consent obtained. Initially, two consecutive patients underwent imaging to ensure the protocol design was robust, and then four additional consecutive patients underwent imaging. Four patients had three-vessel disease, one had two-vessel disease, and one had single-vessel disease. Three subjects had a clinical history and electrocardiographic evidence of Q wave myocardial infarction. One patient had undergone coronary artery bypass grafting. The mean body mass index of the patients was 28.47 kg/m² (range, 26.29–31.71 kg/m²). Mean global ejection fraction at ventriculography was 30.3% (range, 27%–39%).

MR Imaging
Patients underwent MR imaging with a 1.5-T imager (Vision; Siemens Medical Systems, Erlangen, Germany) with gradient amplitude of 25 mT/m and a phased array cardiac coil. Perfusion was assessed with a dynamic inversion-recovery, snapshot, fast low-angle shot, or FLASH, imaging sequence (repetition time msec/echo time msec/inversion time msec = 4.5/2/300, field of view of 300 x 300 mm, section thickness of 9 mm, 96 x 128 matrix, 25 measurements, time resolution pseudogated to approximately every third R-R interval). Images were acquired in the basal, midpapillary, and apical short-axis planes. A bolus of gadodiamide (0.025 mmol per kilogram of body weight) (Omniscan; Nycomed Amersham, Amersham, UK) was given after the third measurement. Images were acquired at rest and during adenosine infusion (140 µg/kg/min for 6 minutes). Contractile function was assessed by using a breath-hold, cine, gradient-echo sequence (60/4.8; field of view of 420 x 315 mm; section thickness of 6 mm; 96 x 128 matrix; acquisition over 15, 19, or 23 heart beats) at rest and after a two-step, steady-state, low-dose dobutamine infusion (first 5 and then 10 µg/kg/min). Images were acquired in the three short-axis planes and in horizontal and vertical long-axis planes (Fig 1). Pulse, blood pressure, and cardiac rhythm were monitored continuously throughout imaging. The time sequence of the protocol is shown in Figure 2.

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   Figure 1. (a-e) Cine images show derivation of imaging planes. In a, the vertical long axis is used to obtain the short-axis views. The three parallel lines indicate the imaging planes for the short axes in three levels: left, basal (in b); middle, midpapillary (in c); and right, apical (in d). In e, the midpapillary short axis is bisected to give the horizontal long-axis view.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Schematic depicts the time sequence for the combined perfusion and function stress MR imaging protocol.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Diagrams depict the division of the left ventricle into ROIs (1-8). Left, perfusion short axis; middle, cine short axis; right, cine long axis.

Data Display
Data display was performed by the principal investigator (P.R.S.). The regional cine and perfusion data were transcribed onto polar maps (Fig 4) of the left ventricle with the outer ring representing the LV basal short-axis section and the inner ring, the apical short-axis section. On the perfusion maps, a second ring, indicated by a dashed inner border, was added to each level to display epicardial and subendocardial data. A further polar map (Fig 5) was overlaid with the Green Lane diagram to facilitate division of the left ventricle into the three coronary artery territories according to the specific coronary artery anatomy of each patient. The presence of any abnormalities detected on the cine and perfusion short-axis MR images for each vascular territory was recorded.

View larger version (78K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Polar maps display regional cine and perfusion data from two patients with an anterior myocardial infarction. a maps, Resting systolic wall thickening (SWT). b maps, Evaluation from resting and stress systolic wall thickening. c maps, Evaluation from resting and stress perfusion images. In the a maps for both patients, anteroseptal thickening at rest is absent. In the b maps, hibernating myocardium is seen in patient 1 but the infarction area is predominantly scar tissue in patient 2; in the c maps, the associated perfusion defect has some reversibility in patient 1 but is fixed in patient 2. In the a and b maps, the concentric rings from outside to inside represent the cine short-axis sections: basal, papillary, and apical. In the c maps, they represent perfusion basal epicardium and subendocardium (inner dashed line), papillary epicardium and subendocardium (inner dashed line), and apical epicardium and subendocardium (inner dashed line).

View larger version (46K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Left: Polar map shows MR imaging ROIs (green) overlaid with adaptation of a Green Lane diagram (black) for the coronary artery anatomy of a patient with occluded left anterior descending (LAD) and right coronary (RCA) arteries and circumflex artery (Cx) disease. The percentage of stenoses (indicated with X) is stated. The red lines indicate coronary artery anatomy: solid, anterograde flow; dotted, poor anterograde filling; dashed, retrograde filling. Right: Polar map depicts the division of MR imaging ROIs (green) into coronary artery territories in this patient. The circumflex coronary artery is dominant and supplies the majority of the inferolateral wall. The small right coronary artery supplies very little myocardium.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

In all six patients, all cine and perfusion images were accepted by the reviewers as being of satisfactory quality for interpretation. Sufficient quality for diagnosis was achieved in 285 of 288 (98.9%) ROIs on perfusion images and in 467 of 468 (99.8%) ROIs on the cine images.

A summary of the results of cine and perfusion MR image analysis is displayed with the angiographic findings in Table 3.

The remaining three (17%) territories were supplied by coronary arteries that were angiographically normal or had a stenosis of less than 50%. In two of these territories, cine and perfusion abnormalities were associated with extension of infarction into a portion of the area from an adjacent affected territory. The remaining portions of these two areas were normal. The third territory supplied by an angiographically normal artery showed some evidence of occult subendocardial ischemia.

Transmural Extent and Reversibility of Ischemia
On the stress images, evidence of abnormal perfusion was seen in 103 of 144 (71.5%) regions. A full-thickness transmural deficit was seen in 40 of 144 (27.8%) ROIs. A perfusion defect limited to the subendocardial layer was identified in 63 of 144 (43.8%) ROIs. Reversibility of the defect was seen in 68 of 144 (47.2%) ROIs, in 57 of 63 (90%) ROIs with subendocardial perfusion deficits, and in 11 of 40 (28%) ROIs with full-thickness deficits. An example of perfusion images that demonstrated a reversible subendocardial perfusion pattern is shown in Figure 6.

View larger version (63K): [in this window] [in a new window] [Download PPT slide]   Figure 6. Resting (top row) and stress (bottom row) perfusion images obtained in a patient with severe right coronary and circumflex artery stenoses. The bolus of gadodiamide (arrow in two images on the left in the top and bottom rows) appears first in the right ventricle (RV) and then in the LV cavity and enhances normally perfused myocardium. There is an impression of hypoenhancement on the inferior surface of the myocardium on the resting images (arrowhead in the top row). The stress images reveal an extensive subendocardial perfusion defect (arrowheads in the bottom row).

Global and Regional LV Function
Global resting LV function was reported as normal in one patient, mildly impaired in one patient, moderately impaired in one patient, and severely impaired in three patients. Of the 144 short-axis resting cine ROIs, 75 of 144 (52.1%) showed normal systolic wall thickening, and 17 of 144 (11.8%) mildly impaired thickening. Fifty-two ROIs demonstrated severe dysfunction, with 23 of 144 (15.9%) showing severely reduced wall thickening and 29 of 144 (20.1%) absent wall thickening. A full-thickness perfusion deficit (ie, present in both epicardial and subendocardial layers) was seen in 29 of 52 (56%) of the severely dysfunctional ROIs compared with five of 92 (5%) ROIs with normal or mildly impaired baseline function. A subendocardial deficit alone was seen in a further 10 of 52 (19%) dysfunctional ROIs and in 43 of 92 (47%) ROIs with normal or mildly reduced resting contractility.

Contractile Reserve
With use of the short-axis and long-axis apical ROIs, 55 of 150 (36.7%) ROIs were identified as having severely reduced or absent wall thickening or wall thinning at resting cine MR imaging. At cine imaging, improved contractility with 5 and/or 10 µg/kg/min dobutamine (ie, a contractile reserve) was demonstrated in 27 of 55 (49%) ROIs (Fig 7). A contractile reserve could not be induced in 25 of 55 (45%) ROIs. Deteriorating function in stress occurred in three of 55 (5%) ROIs. Figure 4 shows the polar maps from two patients with previous anterior myocardial infarction. Both patients had extensive anteroseptal impairment of systolic wall thickening at rest. In patient 1, cine MR images demonstrated myocardial hibernation within the infarction area. Some reversibility of the perfusion defect was also noted. In contrast, the infarction in patient 2 was shown to consist predominantly of scar tissue with a fixed perfusion defect.

View larger version (56K): [in this window] [in a new window] [Download PPT slide]   Figure 7a. (a) Resting and (b) stress horizontal long-axis cine images show diastolic (left) and systolic (right) frames obtained in a patient with resting apical dysfunction (arrow in a). In b, an apical contractile reserve is demonstrated (arrow).

View larger version (54K): [in this window] [in a new window] [Download PPT slide]   Figure 7b. (a) Resting and (b) stress horizontal long-axis cine images show diastolic (left) and systolic (right) frames obtained in a patient with resting apical dysfunction (arrow in a). In b, an apical contractile reserve is demonstrated (arrow).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

All MR images were of sufficient diagnostic quality for interpretation despite the presence of LV dysfunction and a greater than average body mass index in all patients and mild artifact from sternal sutures in the patient with previous bypass surgery. Regional perfusion was not assessable in only three of 288 ROIs owing to an extremely thin lateral wall, which made distinction of the myocardium from the pericardial structures difficult in one patient.

MR Imaging Protocol
There is no single stress agent that optimizes the detection of hibernating myocardium and provides maximal vasodilation for the assessment of resting and stress perfusion. Dobutamine is an ideal inotropic agent for contractile reserve evaluation. In this study, we used a multistep low-dose protocol to ensure a segment that demonstrated a contractile reserve at 5 µg/kg/min but became ischemic at 10 µg/kg/min was not overlooked by imaging at only 10 µg/kg/min. Dobutamine produces a twofold vasodilatory effect (20). Adenosine, however, has little inotropic effect but produces maximal hyperemia (fivefold) (21). Both of these agents have very short half-lives—dobutamine, 2 minutes; adenosine, 2–10 seconds—which ensures any side effects are short lived. These properties make these agents ideal for use in a combined protocol to optimize vasodilation for perfusion imaging and inotropic stimulation for assessment of contractile reserve. The time sequence of the MR imaging protocol allowed maximum temporal separation of the two agents. The resting perfusion study was performed 15 minutes after the stress perfusion study to allow the initial bolus of gadodiamide to clear from the system. A low dose of gadodiamide was used to reduce this time period and also to facilitate future quantitative assessment of the signal intensity changes (12,22).

Site of Ischemia
The patient group had severe coronary artery disease, which resulted in widespread perfusion and wall-thickening abnormalities. Although this study included only a few patients, there appeared to be a high sensitivity for detection of coronary artery stenoses with use of both perfusion and cine modalities. This is despite the fact that the dose of dobutamine in this protocol was kept low deliberately in order to detect hibernating myocardium. Perfusion is likely to be a more sensitive parameter for the identification of ischemic myocardium, because hypoperfusion is an earlier pathophysiologic event than impaired contractility in the ischemic cascade (23). However, the combination of stress perfusion and cine imaging appears to be more sensitive than one modality alone.

Transmural Extent and Reversibility of Ischemia
A valuable feature of MR imaging is its ability to depict the different myocardial layers because of the high spatial resolution. This allows differentiation between subendocardial and transmural perfusion defects. Subendocardial ischemia is thought to be the first indication of myocardial compromise when blood flow is impaired. It has been demonstrated in animal models (24), but its diagnosis in humans is difficult as established modalities such as ²⁰¹Tl scintigraphy and PET do not have sufficient spatial resolution to distinguish between the epicardial and subendocardial layers.

In our patients, subendocardial perfusion defects were seen in coronary territories supplied by stenotic but nonoccluded vessels or by occluded vessels with well-developed collateral support. Subendocardial perfusion defects tended to be reversible and were also associated with segments that showed normal or only mildly reduced resting contractility. Full-thickness perfusion deficits tended to be fixed and associated with severe resting dysfunction.

By using the polar maps, the anatomic extent of these abnormalities could be readily appreciated.

Evaluation of Inducible Contractile Reserve
Areas of existing myocardial injury were clearly identified on the resting cine images. In the ROIs identified as showing severe resting dysfunction, the presence or absence of a contractile reserve was readily assessed with no disagreement between reviewers.

In Figure 4, images obtained in two patients demonstrate the potential of the protocol for clinical application. Both patients had sustained large Q wave infarctions in the territory of the left anterior descending artery and had an occluded vessel at angiography. Severe dysfunction was seen at resting cine MR imaging. In patient 1, reversible ischemia was seen within the infarction zone and a large area demonstrated a contractile reserve, which suggested a large amount of hibernating myocardium was present. In contrast, patient 2 had a large fixed perfusion deficit with only a small area of reversibility at the infarction edge. A rim of myocardial hibernation was identified, but the majority of the infarction area was demonstrated to be scar tissue. The results from stress MR imaging demonstrate that patient 2 would be unlikely to benefit from revascularization and would have a major surgical risk, but patient 1 had potential for LV functional recovery and a good outcome after revascularization.

In conclusion, we found that this combined stress MR imaging technique is safe, feasible, well tolerated, and clinically applicable. High-quality information was provided about both myocardial function and perfusion with use of a standard clinical MR imager. This information is complementary to angiographic data and more comprehensive than that obtained with any currently available noninvasive investigative techniques. Thus, a detailed evaluation of patients with coronary artery disease prior to revascularization can be achieved with MR imaging.

	Footnotes

 
Abbreviations: LV = left ventricular ROI = region of interest

Author contributions: Guarantor of integrity of entire study, G.R.C.; study concepts, P.R.S., D.d.B.; study design, P.R.S., A.J.; definition of intellectual content, P.R.S., G.R.C., N.J.S.; literature research, P.R.S.; clinical studies, P.R.S., A.J., R.P.K.; data acquisition, P.R.S., A.J., J.L.T.; data analysis, P.R.S., N.M.H., R.P.K., B.M., G.R.C.; manuscript preparation, P.R.S.; manuscript editing, G.R.C., N.J.S.; manuscript review, A.J., N.M.H., R.P.K., B.M.

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