In patients with known or suspected myocardial ischemia, noninvasive techniques are necessary not only to establish or exclude the presence of coronary artery disease but also to define management and prognosis (1- 2). Cardiovascular magnetic resonance imaging (CMR) is becoming an integral part of the diagnostic workup of patients with ischemic heart disease (1).

So far, the usefulness of vasodilator stress CMR for predicting clinical events has not been proven. The purpose of the present study was to determine the prognostic value of dipyridamole stress CMR in patients with known or suspected ischemic heart disease.

The study population was represented by 420 consecutive patients with chest pain of possible coronary origin who underwent dipyridamole stress CMR between January 2003 and January 2006 owing to inconclusive exercise testing (18%), altered electrocardiogram (22%), inability to exercise (23%), evaluation of the severity of intermediate lesions (10%), and first choice (27%).

Exclusion criteria were a history of myocardial infarction or coronary revascularization within the last 3 months, hemodynamic instability, asthma, and a follow-up duration of <6 months.

All data were prospectively recorded. The study protocol was approved by an ethics committee, and all subjects gave informed consent.

All patients were examined with a 1.5-T system (Sonata Magnetom, Siemens, Erlangen, Germany). All images were acquired by a phased-array body surface coil during breath holds and were electrocardiogram triggered.

Left ventricular function was assessed using cine images in 2-, 3-, 4-chamber, and short-axis views using a true fast imaging with steady-state precession sequence (TrueFISP) (repetition time/echo time 2.8 ms/1.2 ms, flip angle 58°, matrix 256 × 256, field of view 320 × 270 mm, slice thickness 6 mm).

Vasodilatation was induced with dipyridamole (0.84 mg/kg body weight) delivered intravenously over 6 min. Two minutes after the end of dipyridamole infusion, 0.1 mmol/kg gadopentate dimeglumine (Magnograf, Schering, Berlin, Germany) was injected intravenously at a speed of 5 ml/s. Then 4 sections equally separated in the short-axis view and 2 in the 2- and 4-chamber long-axis views were acquired for first-pass perfusion imaging (TrueFISP with a notched saturation pulse, inversion time 125 ms, repetition time/echo time 202 ms/1 ms, flip angle 50°, matrix 192 × 96, field of view 350 × 220 mm, slice thickness 8 mm).

Once the peak myocardial enhancement was reached, to assess left ventricular function within the peak dipyridamole-induced vasodilatation (approximately 3 min after infusion) we used a fast-acquisition multislice TrueFISP cine image sequence (repetition time/echo time 35 ms/1.1 ms, flip angle 65°, matrix 192 × 159, field of view 350 × 304 mm, slice thickness 8 mm) acquiring over a 14-s period 4 slices in the short-axis view in the same locations evaluated for cine images at rest.

Late enhancement imaging was performed 10 min after contrast injection in the same locations evaluated for cine images at rest (segmented inversion recovery TrueFISP, repetition time/echo time 700 ms/1.26 ms, flip angle 45°, matrix 256 × 184, field of view 340 × 235 mm, slice thickness 8 mm). The inversion time was adjusted to null normal myocardium.

Cardiovascular magnetic resonance studies were analyzed by an experienced observer blinded to all patient data and using customized software (Syngo, Siemens). The 17-segment model was applied (3). We evaluated 4 dipyridamole stress CMR-derived indexes ((Figure 1),6):

The AWM, AWM-D, perfusion deficit, and delayed enhancement were categorized according to the best cut-off value in receiver-operating characteristic curves (0 to 1 segment vs. >1 segment in all cases) to predict major adverse cardiac events (MACE) during follow-up. In our laboratory, interobserver agreement concerning these 4 CMR indexes is >90%.

A CMR study-related cardiac catheterization (within the subsequent 3 months) was carried out in 145 patients. A CMR study-related revascularization was performed in 80 patients: percutaneous coronary intervention in 65 and coronary artery bypass grafting in 15 (Table 1).

The primary end point was MACE and included cardiac death, nonfatal myocardial infarction, and admission for unstable angina (whichever occurred first). All MACE were reviewed, and consensus between 2 cardiologists was required to finally designate a MACE. Admission for unstable angina required the presence of chest pain with unstable characteristics leading to hospital admission and evidence of abnormal coronary angiography.

The secondary end point was major events (cardiac death or nonfatal myocardial infarction, whichever occurred first).

Continuous data were expressed as the mean ± standard deviation and were compared by the unpaired t test. Proportions were compared by the chi-square statistic; the Fisher exact test was used when appropriate. Survival distributions for the time to event were estimated using the Kaplan-Meier method and the log rank test.

The association of variables with MACE and major events was assessed with the Cox proportional hazard regression model using stepwise multivariate procedures. Variables with a p value of <0.1 in the univariate analysis in (Tables 1, 2, 3, 4) were tested in multivariate procedures. A significance of 0.05 was required for a variable to be included in the final multivariate model. Hazard ratios with the corresponding 95% confidence intervals were estimated. The predictive ability of the Cox models was assessed by estimating the Harrell C-statistics before and after the addition of CMR data.

Statistical significance was considered to be p < 0.05. The SPSS 11.0 (SPSS, Chicago, Illinois) and STATA 9.0 (StataCorp, College Station, Texas) computer programs were used throughout.

All patients were followed up for at least 6 months (495 ± 309 days, range 184 to 1,372 days, median 420 days); 41 MACE including 23 major events (9 cardiac deaths and 14 nonfatal myocardial infarctions) and 18 readmissions for unstable angina were detected. The baseline characteristics are shown in (Tables 1, 2).

Patients with MACE had a worse clinical profile (Table 1). In the univariate analysis, all dipyridamole stress CMR indexes evaluated were related to MACE ((Table 2), Figures 2, 3).

In the multivariate analysis, the extent of AWM-D was the only dipyridamole stress CMR index independently related to MACE (Table 5).

The C-statistic of the model with baseline characteristics included in (Table 1) (0.795) was improved by the addition of CMR data included in (Table 2) (0.812).

Patients with major events had a worse clinical profile (Table 3) and a larger extent of AWM-rest, AWM-D, perfusion deficit, and delayed enhancement ((Table 4), Figure 2).

In the multivariate analysis, the extent of AWM-D was the only dipyridamole stress CMR index independently related to major events (Table 5).

The C-statistic of the model with baseline characteristics included in (Table 3) (0.779) was improved by the addition of CMR data included in (Table 4) (0.836).

In the 340 nonrevascularized patients, we detected 32 MACE, including 8 cardiac deaths, 11 nonfatal myocardial infarctions, and 13 readmissions for unstable angina.

Similarly to the whole group, the extent of AWM-D was the only dipyridamole stress CMR index independently related to MACE and major events ((Figure 3), Table 5).

We created a 5-step score (from 0 to 4 indexes) according to the number of abnormal CMR indexes detected. The percentage of MACE (2%, 10%, 17%, 16%, and 24%; p < 0.0001 for the trend) and of major events (2%, 6%, 9%, 8%, and 11%; p = 0.06 for the trend) increased with the number of abnormal CMR indexes detected. In the multivariate analysis this score was not selected as an independent variable.

The main finding of the present study is that dipyridamole stress CMR provides independent information for predicting cardiac events in patients with chest pain and known or suspected ischemic heart disease.

Stress CMR is likely to be useful for establishing the prognosis in patients with chest pain and known or suspected ischemic heart disease. However, so far, only dobutamine stress CMR (5- 6) has been proven to be useful. Data concerning the prognostic value of vasodilator stress CMR are scarce (7). The present study is the first to assess the usefulness of vasodilator stress CMR for predicting spontaneous clinical events.

Cardiovascular magnetic resonance imaging allows a comprehensive evaluation of coronary patients (8). In fact, all 4 CMR indexes assessed—AWM-rest, AWM-D, perfusion deficit, and delayed enhancement—related to prognosis.

Only AWM-D afforded independent information: each additional dysfunctional segment increased the risk of events by 15%.

Abnormal wall motion at peak stress integrates the information provided by systolic function at rest plus stress-induced systolic function. This observation is in accordance with studies using nuclear imaging techniques (2), stress echocardiography (9), and dobutamine CMR (5- 6), suggesting that wall motion at peak stress is the most significant predictor of cardiac events.

Quantitative assessment of perfusion is possible but it is time consuming. Moreover, TrueFISP sequences with high dose of contrast offer high image quality, but occasionally transitory artifacts make quantitative assessment difficult. The accuracy of visual analysis, as we did, has been encouraging (1,4).

The prognostic value of perfusion deficit was weaker than that of AWM-D. Revascularization guided by perfusion deficit might partially attenuate the deleterious effect of this finding. However, results were identical after censoring those 80 patients who underwent a CMR study-related revascularization procedure. This reinforces the value of wall motion at stress in relation to the spontaneous evolution of patients.

The role of delayed enhancement for the assessment of myocardial viability (8,10- 11) and the definition of patient outcome (12) is in expansion. However our results suggest that in patients evaluated for chest pain the prediction of clinical events can be improved by the simultaneous assessment of other indexes, especially the extent of systolic dysfunction at stress.

In patients with chest pain and known or suspected ischemic heart disease, dipyridamole stress CMR predicts clinical events over the subsequent months. The extent of abnormal wall motion at stress is the CMR index most closely related to outcome.

For an accompanying video to (Figure 1), please see the online version of this article.

(Top left) Cine images at rest; (top right) cine images at stress; (bottom) first-pass perfusion imaging.