Department of Internal Medicine II - Cardiology, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany
Received 10 July 2004; revised 17 December 2004; accepted 23 December 2004; online publish-ahead-of-print 15 February 2005.
* Corresponding author. Tel: +49 731 500 24441; fax: +49 731 500 24442. E-mail address: vinzenz.hombach{at}medizin.uni-ulm.de
See page 532 for the editorial comment on this article (doi:10.1093/eurheartj/ehi156)
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Abstract |
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Methods and results One hundred and ten patients were studied by MRI 6.1±2.2 days after AMI. Infarct size (IS), persistent microvascular obstruction (PMO), left and right ventricular (LV/RV) volumes, and functions were measured. The same MRI measurements were repeated in 89 patients after a mean follow-up period of 225±92 days. IS was 11.9±7.3% of total LV muscle mass. PMO was detected in 51/110 (46.4%) patients and comprised 15.6±8.5% of IS and 2.8±2.3% of LV muscle mass. Papillary muscle infarct was seen in 26%, RV infarction in 16%, pericarditis in 40%, and pericardial effusion in 66% of the patients. During follow-up, there were 16 major adverse cardiac events (MACE) including seven deaths. IS, PMO, and amount of transmural infarction were predictive for LV adverse remodelling defined as >20% increase in LV end-diastolic volume. Multivariable analysis revealed LV end-diastolic volume, LV ejection fraction, and PMO as significant predictors for the occurrence of MACE.
Conclusion MRI is a highly sensitive and reliable tool to detect morphologic and functional sequelae of AMI providing baseline MRI parameters with relevant predictive power for LV adverse remodelling and occurrence of MACE.
Key Words: Magnetic resonance imaging Infarct size Microvascular obstruction Myocardial viability Right ventricular infarction Coronary heart disease
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Introduction |
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In some patients, the no-reflow or low-flow phenomenon occurs despite early recanalization of the infarct-related artery by thrombolysis or coronary angioplasty,7 most probably due to simultaneous damage and necrosis of both myocytes and capillaries in the centre of the infarct region. Experimental and clinical studies showed that microvascular obstruction (MO) is associated with greater myocardial damage and poorer global ventricular function in the early post-infarction phase.8,9
Right ventricular (RV) and pericardial involvement during AMI and their possible consequences are not in the main focus of treating patients with AMI, as these complications only become evident in case of a haemodynamic compromise, although a higher mortality has been reported in patients with RV infarction.10,11 On the basis of clinical and echocardiographic data, pericarditis during AMI is associated with larger and transmural infarctions.12,13 Both the true incidence of minor degrees of RV infarcts and pericarditis in patients with AMI in the era of revascularization therapy is unknown.
Owing to the high tissue contrast and spatial resolution of cardiac MRI, this study was performed in patients with AMI to discover infarct-related alterations of cardiac structure and function during the acute phase of myocardial infarction and the consequences of infarct healing on these parameters, including their prognostic significance.
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Methods |
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Follow-up MRI was planned in the range of 69 months after AMI and performed after a mean follow-up of 268±94 days (median 251, lower quartile 195, upper quartile 308) in 89 patients with the identical protocol as before. The study protocol was approved by the local Ethics Committee. All subjects gave their written informed consent.
MRI protocol and data analysis
MRI was performed on a 1.5 T whole body scanner (Intera CV, Philips Medical Systems, Best, The Netherlands). To define the position and axis of the left ventricle, three short survey scans were performed. Parallel imaging was employed for all scans.14 Resting LV and RV function was determined with cine images using a segmented k-space balanced fast-field-echo sequence (steady-state-free-precession) in short and long axis views in the true heart axis. Depending on the field-of-view, in-plane resolution was between 1.5x1.8 mm2 and 2.3x1.8 mm2 with a slice thickness of 10 mm for the functional scans. The short axis scans covered the whole LV and RV with 1014 contiguous slices. LV- and RV- ejection fractions (EFS) and volumes were determined using short axis volumetry, as previously described.15
For the first-pass perfusion, a balanced turbo-field-echo sequence with three short axis slices per heartbeat (prospective triggering) and a selective saturation recovery pre-pulse (delay 130 ms) before each slice was used. Slice thickness was 10 mm. The typical in-plane resolution was 2.8x3.0 mm. In order to achieve post-contrast conditions comparable to a stress/rest perfusion protocol, this sequence was conducted twice with 0.1 mmol/kg body weight gadolinium-diethylene-triamine-pentaacetic acid, injected into an antecubital vein by a power injector (Medrad Spectris, Volkach, Germany) at a rate of 6 mL/s.
After 612 min, a late enhancement (LE) analysis using a 3D-gradient spoiled turbo fast-field-echo sequence with a selective 180° inversion recovery pre-pulse was acquired in the short axis covering the whole left ventricle (2022 5 mm slices). Two to three long axis views with a similar 2D-sequence were additionally performed. An initial pre-pulse delay of 225 ms was applied and the measurement was repeated if contrast was not favourable with an adjusted pre-pulse delay. The typical examination time was 4560 min.
Wall motion abnormalities were visually classified as hypo-, dys-, or akinetic and documented on the usual 17-segment model. Regional hypoperfusion on first-pass was visually assessed and documented using the same model. Infarct size (IS) was defined as an area of late hyper-enhancement on LE images of the AMI. Persistent microvascular obstruction (PMO) was defined as late hypo-enhancement within a hyper-enhanced region on LE images (Figure 1).16 IS and PMO were quantified on the 3D-volume by manual delineation of the enhanced and unenhanced myocardium with different contours (MASS plus 5.0, Medis, Leiden, The Netherlands). PMO was included in the IS quantification. Papillary muscles were assigned to the myocardium and binary judged as infarcted or not. Pericarditis was defined as increased signal intensity of the pericardium post-contrast (Figure 3).1719 Pericardial effusion was diagnosed on cine steady-state-free-precession sequences. In uncertain cases, T1- and T2-weighted black blood turbo-spin-echo sequences (with and without fat saturation pre-pulse) were additionally performed to distinguish effusion from pericardium, epicardium, and epicardial fat.
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Follow-up
Patients were followed by an intern questionnaire used previously21 for CCS-status, medication, and major adverse cardiac events (MACE) at the time of the intended second MRI study. MACE were defined as death, myocardial infarction, re-hospitalization for cardiac failure, unstable angina, or revascularization [PCI or coronary artery bypass grafting (CABG)]. The follow-up interviewer was not aware of the results of the MRI studies.
Statistics
There was no sample size calculation. Summary values are expressed as means ± standard deviation. Categorical data were compared by the 2 test. Differences between means of continuous variables were analysed using the Student's t-test. We used the Holm method to account for type I error due to multiple testing.22 Survival curves for MACE were calculated according to KaplanMeier. Statistical significance was tested with the log-rank test (Statistica version 6.0, StatSoft Incorporation, Tulsa, OK, USA). Pearson's correlation coefficients (r) were calculated with StatXact (version 6.0, Cytel Software Corporation, Cambridge, MA, USA) as exact test. All tests were two-sided. P-values below 0.05 were considered as statistically significant.
Subgroups of patients, differentiated by the presence or absence of PMO and according to the median of IS, were compared. We performed multivariable receiver operator characteristics (ROC) analysis (Matlab)23 to test the diagnostic value in terms of adverse remodelling of following baseline MRI parameters: LV end-diastolic volume (EDV), LV end-systolic volume (ESV), LVEF, infarct localization (anterior vs. not anterior), amount of transmural infarction in per cent of total IS. Parameter combination was done using Fisher's discriminate. Adverse remodelling was defined as an increase in LVEDV from baseline to follow-up MRI measurement of 20% according to Mannaerts et al.24 The best combination of three parameters was defined as being the one with the maximal area under the ROC curve. We performed a Cox regression to evaluate variables with potential impact on the occurrence of MACE. We included the baseline MRI parameters LVEDV, LVESV, LVEF, PMO, IS, and transmural infarction in per cent of total infarct. For reasons of co-linearity, variables with a correlation coefficient greater than 0.4 were not considered in the subsequent analysis. Survival curves were estimated by the KaplanMeier method. The log-rank test was used to compare survival curves from the groups of patients with and without PMO and for the groups of patients according to the median of IS. Confidence intervals for estimated event rates were calculated according to Altman et al.25
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Results |
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Subgroups
Baseline MRI morphologic and functional MRI parameters (RV- and LV-volumes, LVEF, PMO size, IS) did not statistically differ between the groups of patients with primary (n=81) or delayed PCI (n=16) or with non-interventional treatment (n=13). However, patient numbers in all groups were low and the treatment options run from optimal to non-optimal.
Comparison of baseline data, MRI data as well as follow-up results between patients with and without PMO are given in Table 3. The following parameters were compared between the groups: LVEF and IS at baseline and at follow-up, maximal creatine kinase, and MACE. Patients with PMO had a significantly higher maximal creatine kinase, a significantly larger IS, and a lower LVEF both at baseline and at follow-up, and a trend towards a higher occurrence rate of MACE.
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In patients with both MRI measurements, IS decreased from 11.4±7.2 to 7.8±5.3% (P<0.00001). IS was significantly smaller in patients without PMO when compared with patients with PMO, both at baseline (8.0±5.2 vs. 15.5±7.2%, P<0.00001) and at follow-up (6.1±4.5 vs. 9.8±5.4%, P=0.00064) (Figure 4A). In addition, shrinkage of IS was significantly higher in patients with PMO compared with patients without PMO (35.6±22.7 vs. 22.0±28.7%, P=0.017). No PMO was seen at follow-up. LVEF and LVEDV increased and LVESV decreased during follow up (Figure 4BD). The mean number of segments with wall motion abnormalities decreased from 5.0±2.4 to 3.7±2.5 (P<0.00001). Values of MRI parameters between patients with and without PMO are given in Table 3.
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Patients (n=6) with cardiac death during follow-up had a lower LVEF (41.5±8.3 vs. 58.1±10.0%), a larger IS (15.7±10.1 vs. 11.7±7.2%), and a larger amount of PMO (3.6±3.2 vs. 1.2±2.2%) at baseline MRI compared with surviving patients.
Survival rate was significantly higher in the primary PCI group and delayed PCI group compared with the conservatively treated group (97.5, 93.8, and 61.5%, respectively; P<0.00001).
Cox regression analysis revealed LVEF (P=0.0057), LVEDV (P=0.038), and PMO (P=0.044) as significant predictors for the occurrence of MACE (total model P=0.0074).
KaplanMeier survival curves revealed a significant better event-free survival for patients without PMO and a trend in patients with smaller IS (Figure 5). At 100 days' follow-up, the difference in occurrence of MACE between patients with and without PMO was 12.6% (95% confidence interval 1.423.8%) and in patients regarding median IS was 5.4% (95% confidence interval, 4.915.6%).
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Discussion |
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IS comprised a mean of 12% (0.732%) of LVMM and displayed a regular shrinkage of relative 28% at follow-up during optimal evidence-based drug therapy. Patients with larger infarcts by LE showed a higher LVESV, LVEDV, and a lower LVEF both at baseline and at follow-up MRI study, more pericardial effusion, and RV infarcts compared with patients with smaller IS.
PMO comprised 16% of IS and always disappeared on infarct healing. The significantly positive correlation between the extent of PMO and IS and the significantly higher shrinkage of IS in patients with PMO may be explained by a larger amount of necrosis in these patients resulting in a thinner fibrous scar and an increased amount of negative remodelling. The predictive impact of IS and PMO is strengthened by the finding that the combination of IS, PMO, and transmural infarction was most predictive for the occurrence of adverse remodelling. These results are not biased by ventricular remodelling per se, since this process should be completed after 5 months post-AMI, which was the shortest interval of the second MRI study in our series.
The earlier mentioned findings compare well with experimental and clinical data: the larger the infarct, the worse are the global and regional ventricular functions, and the higher the rate of LV remodelling and adverse events during follow-up of the patients.26 In our study, survivors had, at baseline MRI measurement, a better cardiac function and a lower PMO and IS than patients suffering from cardiac death.
We defined MO as persistent late-hypo-enhancement within a hyper-enhanced area. Recently, Lund et al.16 reported a high concordance between MO on first-pass enhancement MR images and MO on delayed enhancement MR images defined as late hypo-enhancement. They found a correlation of 0.71. The sensitivity of delayed enhancement MR images was 74% for the detection of MO with first-pass enhancement MR images used as the reference standard. They discussed that the difference could be explained by a filling of the early hypo-enhancement over time by contrast material, through collateral flow, or by slow diffusion. A contrast filling of an area accused to have MO implies the requirement of an at least minimal residual blood flow. If there is complete obstruction of the microvasculature (= no-reflow) due to thrombotic material within the vessel or due to tissue or vessel wall swelling after AMI, there has to be no contrast filling in this area over time. Here, our intention was to report on the amount of MO which is definitely not filled by contrast material, which focuses our analysis on severe cases with persistent contrast filling defects. In our study, all areas with late hypo-enhancement were surrounded by late hyper-enhancement, indicating a persistent area of non-perfusion compatible with severe PMO, which has been mentioned previously.27,28 The impact of PMO is stressed by our results. The evidence of PMO was associated with an increased risk of the occurrence of MACE. Frequency of occurrence of MACE was 8.4% (n=5/59) in patients without PMO and 21.6% (n=11/51) in patients with PMO. In the multivariable analysis of MRI baseline parameters to predict adverse remodelling, the combination included PMO. In cox regression analysis, PMO was a predictor for the occurrence of MACE.
Wu et al.9 analysed MO defined as early hypo-enhancement in 44 AMI patients (eight patients with primary PCI, 20 patients with elective PCI >48 h). In patients with MO, more cardiovascular events occurred than in those without MO and microvascular status predicted the occurrence of cardiovascular complications. The combined risk of cardiovascular death, re-infarction, congestive heart failure, or stroke increased with infarct extent (30, 43, and 71%, respectively) for small, mid-sized, and large infarcts. Even if the analysis was adjusted for IS, the presence of MO remained a prognostic marker for post-MI complications. In our study, LVEF, LVEDV, and MO were predictors for the occurrence of MACE.
The incidence of further morphologic sequelae was higher than expected: papillary muscle infarct was seen in 26%, RV involvement by LE in 17%, and by regional wall motion abnormalities in 43%. These patients had minor wall motion abnormalities within the septal part of the RV without a relevant functional impairment. These subtle findings were not yet described in the literature, which generally resumes that RV infarction correlates to 50% to inferior infarction due to proximal RCA occlusion and becomes clinically relevant with cardiac failure. Bueno et al.10 studied 198 elderly patients with inferior AMI receiving acute reperfusion therapy (PCI or thrombolysis) in only 25%. In the RV infarction group, mortality was 47% and cardiogenic shock occurred in 32%, compared with 10 and 5% for patients without RV infarction, respectively. Zehender et al.11 reported a 31% in-hospital mortality rate in AMI patients with RV infarction, compared with 6% in those without. Thrombolytic therapy was given in 36% of patients, who were admitted within 6 h after onset of AMI and
75 years old. In our study, RV infarction detected by LE was not associated with a worse outcome, although it was found predominantly in patients with larger infarcts. This may be due to the generally preserved RV performance due to early recanalization therapy. This is supported by the data of Giannitsis et al.29 showing that in-hospital mortality after early recanalization therapy in patients with RV infarction is not increased when compared with patients without RV involvement.
Post-infarction pericarditis is known to occur with transmural or near transmural infarction and to be localized at the infarct's apex on the epicardium,12,13 whereas the post-MI syndrome (Dressler syndrome) does not require transmural infarction. Using MRI we observed a much higher incidence of pericarditis (40%) and pericardial effusion (66%) of subclinical degree without a significant influence on the acute clinical course of the patients.
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Limitation |
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Conclusion |
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Acknowledgement |
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Footnotes |
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JW and HAK should both be considered senior authors.
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References |
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