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J Am Coll Cardiol, 2007; 50:1174-1179, doi:10.1016/j.jacc.2007.06.016 (Published online 31 August 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH

Prognostic Value of Dipyridamole Stress Cardiovascular Magnetic Resonance Imaging in Patients With Known or Suspected Coronary Artery Disease

Vicente Bodi, MD, FESC*,*, Juan Sanchis, MD, FESC*, Maria P. Lopez-Lereu, MD{dagger}, Julio Nunez, MD*, Luis Mainar, MD*, Jose V. Monmeneu, MD{dagger}, Oliver Husser, MD*, Eloy Dominguez, MD*, Francisco J. Chorro, MD, FESC* and Angel Llacer, MD, FESC*

* Cardiology Department, University Clinic Hospital, University of Valencia, Valencia, Spain
{dagger} Exploraciones Radiológicas Especiales Sociedad Anónima, Valencia, Spain

Manuscript received February 27, 2007; revised manuscript received June 5, 2007, accepted June 19, 2007.

* Reprint requests and correspondence: Dr. Vicente Bodi, Cardiology Department, University Clinic Hospital, Blasco Ibanez 17, 46010 Valencia, Spain. (Email: vicentbodi{at}hotmail.com).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 
Objectives: We evaluated the prognostic value of dipyridamole stress cardiovascular magnetic resonance imaging (CMR) in patients with chest pain and known or suspected coronary artery disease.

Background: Stress perfusion CMR has been incorporated in daily practice. Data on its prognostic value are preliminary.

Methods: Dipyridamole stress CMR was performed in 420 patients with chest pain and known or suspected coronary artery disease. The extent (number of segments according to the 17-segment model) of abnormal wall motion at rest (AWM-rest), abnormal wall motion with dipyridamole (AWM-D), perfusion deficit (at stress first-pass perfusion imaging), and delayed enhancement (at late enhancement imaging) were analyzed.

Results: During a median follow-up of 420 days, 41 major adverse cardiac events (MACE), including 9 cardiac deaths, 14 nonfatal myocardial infarctions, and 18 readmissions for unstable angina with documented abnormal angiography, were documented. The MACE were more frequent in patients with significant (>1 segment) AWM-rest (22% vs. 5%), AWM-D (21% vs. 4%), perfusion deficit (17% vs. 5%), and delayed enhancement (20% vs. 6%; p <0.0001 in all cases). In a multivariate analysis adjusted for baseline characteristics, the extent of AWM-D was independently related to MACE (hazard ratio [HR] 1.15 [95% confidence interval (CI) 1.06 to 1.24] per segment; p = 0.0006) and to major events (cardiac death or nonfatal myocardial infarction; HR 1.15 [95% CI 1.05 to 1.26] per segment; p = 0.002).

Conclusions: Dipyridamole stress CMR is useful for predicting the outcome of patients with known or suspected coronary artery disease.

Abbreviations and Acronyms
  AWM-D = extent (number of segments) of abnormal wall motion with dipyridamole
  AWM-rest = extent (number of segments) of abnormal wall motion at rest
  CMR = cardiovascular magnetic resonance imaging
  MACE = major adverse cardiac events
  TrueFISP = true fast imaging with steady-state precession sequence

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.


   Methods
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 Abstract
 Methods
Results
 Discussion
 Conclusions
 Appendix
 References
 
Study group.   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.

CMR study.   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.

Cine images at rest
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 x 256, field of view 320 x 270 mm, slice thickness 6 mm).

First-pass perfusion imaging
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 x 96, field of view 350 x 220 mm, slice thickness 8 mm).

Cine images at stress
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 x 159, field of view 350 x 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
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 x 184, field of view 340 x 235 mm, slice thickness 8 mm). The inversion time was adjusted to null normal myocardium.

CMR data analysis.   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 (Fig. 1, Online Video 1):

1 Wall motion at rest (AWM-rest): number of segments showing hypokinesis, akinesis, or dyskinesis at baseline.
2 Wall motion with dipyridamole (AWM-D): number of segments showing hypokinesis, akinesis, or dyskinesis at stress.
3 Perfusion deficit with dipyridamole: number of segments showing persistent delay (in at least 3 consecutive temporal images) in the visual analysis of enhancement pattern during the first pass of contrast through the myocardium (4).
4 Delayed enhancement: number of segments showing enhancement in late enhancement imaging.
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%.


Figure 1
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  		Figure 1 Dipyridamole Stress CMR Allows Assessment of AWM-rest and -D, Perfusion Deficit, and Delayed Enhancement

Example of a patient with stress-induced systolic dysfunction and perfusion deficit in the inferior area (arrows) and a small area of delayed enhancement in the anterior territory (bottom right panel, arrow). AWM-D = abnormal wall motion with dipyridamole; AWM-rest = abnormal wall motion at rest; CMR = cardiovascular magnetic resonance imaging.

Please see the Appendix for accompanying video.

 
Cardiac catheterization.   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).


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  		Table 1 Baseline Characteristics of the Whole Study Group and of Patients With and Without MACE
 
End points and follow-up.   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).

Statistical analysis.   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 to 4 GoGoGo 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.


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  		Table 2 Cardiovascular Magnetic Resonance Imaging Data of the Whole Study Group and of Patients With and Without MACE
 

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  		Table 3 Baseline Characteristics of Patients With and Without Major Events in the Whole Study Group
 

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  		Table 4 Cardiovascular Magnetic Resonance Imaging Data of Patients With and Without Major Events in the Whole Study Group
 
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.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 Conclusions
 Appendix
 References
 
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 and 2.

MACE.   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, Figs. 2 and 3).Go


Figure 2
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  		Figure 2 MACE and Major Events Depending on the Presence or Absence of Abnormal (≥1 Segment) Stress Dipyridamole CMR Indexes in the Whole Group

AWM-D = number of segments with abnormal wall motion with dipyridamole; AWM-rest = number of segments with abnormal wall motion at rest; CMR = cardiovascular magnetic resonance imaging; MACE = major adverse cardiac events.

 

Figure 3
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  		Figure 3 Kaplan-Meier Survival Distributions Without MACE Based on the Presence or Absence of Abnormal Wall Motion With Dipyridamole

(Top) Unadjusted curves; (bottom) survival curves adjusted for diabetes, hypertension, and previous infarction; (left) whole group; (right) nonrevascularized patients. Dashed lines = presence (≥1 segment) of abnormal wall motion with dipyridamole; solid lines = absence (0 to 1 segment) of abnormal wall motion with dipyridamole. AWM-D = number of segments with abnormal wall motion with dipyridamole; MACE = major adverse cardiac events.

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


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  		Table 5 Independent Predictors of MACE and Major Events in the Whole Study Group and in Nonrevascularized Patients
 
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).

Major events.   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, Fig. 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).

Nonrevascularized patients.   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 (Fig. 3, Table 5).

Combination of CMR indexes.   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.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Conclusions
 Appendix
 References
 
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 and prognosis of coronary artery 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.

Wall motion at stress.   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.

Perfusion imaging.   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.

Late enhancement imaging.   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.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
Appendix
 References
 
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.


   Appendix
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
 Appendix
References
 
For an accompanying video to Figure 1, please see the online version of this article.


   Footnotes
 
This work was supported by the grant Bayer 2007 from the Spanish Society of Cardiology.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 

  1. Barkhausen J, Hunold P, Jochims M, Debatin JF. Imaging of myocardial perfusion with magnetic resonance J Magn Reson Imaging 2004;19:750-757.[CrossRef][ISI][Medline]
  2. Schuijf JD, Poldermans D, Shaw LJ, et al. Diagnostic and prognostic value of noninvasive imaging in known or suspected coronary artery disease Eur J Nucl Med Mol Imaging 2006;33:93-104.[CrossRef][ISI][Medline]
  3. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart Circulation 2002;105:539-542.[Free Full Text]
  4. Cury RC, Cattani CA, Gabure LA, et al. Diagnostic performance of stress perfusion and delayed enhancement MR imaging in patients with coronary artery disease Radiology 2006;240:39-45.[Abstract/Free Full Text]
  5. Hundley WG, Morgan TM, Neagle CM, Hamilton CA, Rerkpattanapipat P, Link KM. Magnetic resonance imaging determination of cardiac prognosis Circulation 2002;106:2328-2333.[Abstract/Free Full Text]
  6. Kuijpers D, van Dijkman PR, Janssen CH, Vliegenthart R, Zijlstra F, Oudkerk M. Dobutamine stress MRI. Part II. Risk stratification with dobutamine cardiovascular magnetic resonance in patients suspected of myocardial ischemia Eur Radiol 2004;14:2046-2052.[CrossRef][ISI][Medline]
  7. Ingkanisorn WP, Kwong RY, Bohme NS, et al. Prognosis of negative adenosine stress magnetic resonance in patients presenting to an emergency department with chest pain J Am Coll Cardiol 2006;47:1427-1432.[Abstract/Free Full Text]
  8. Bodi V, Sanchis J, Lopez-Lereu MP, et al. Usefulness of a comprehensive cardiovascular magnetic resonance imaging assessment for predicting recovery of left ventricular wall thickening in the setting of myocardial stunning J Am Coll Cardiol 2005;46:1747-1752.[Abstract/Free Full Text]
  9. Yao SS, Qureshi E, Sherrid MV, Chaudhry FA. Practical applications in stress echocardiographyRisk stratification and prognosis in patients with known or suspected ischemic heart disease. J Am Coll Cardiol 2003;42:1084-1090.[Abstract/Free Full Text]
  10. Bodi V, Sanchis J, Lopez-Lereu MP, et al. Microvascular perfusion one week and six months after myocardial infarction by first-pass perfusion imaging CMR Heart 2006;92:1801-1807.[Abstract/Free Full Text]
  11. Bodi V, Sanchis J, Lopez-Lereu MP, et al. Evolution of five cardiovascular magnetic resonance imaging-derived viability indexes after reperfused myocardial infarction Am Heart J 2007;153:649-655.[CrossRef][ISI][Medline]
  12. Kwong RY, Chan AK, Brown KA, et al. Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery diseaseLate enhancement and prognosis. Circulation 2006;113:2733-2743.[Abstract/Free Full Text]



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This Article
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