The main finding is that contrast enhanced CE-SSFP CMR evaluation of MaR correlates well with angiographic jeopardy scores validated previously as surrogates for clinical outcome [
22]. The bias was small with very mild overestimation, 1.1 and 1.2% for the BARI and Modified APPROACH scores respectively. The limits of agreement between the CMR and angiographic measurements were -11.4 to +9.1, and -13 to +10.5 for the BARI and Modified APPROACH scores respectively. There was consistent variability across the range of MaR measured.
Final infarct size in acute STEMI is a key determinant for clinical outcome and has to be determined in relation to MaR [
1,
2]. Due to the large variability in absolute infarct size, very large study groups are needed to achieve adequate power in clinical studies having infarct size as an end-point. Myocardial salvage is a pragmatic surrogate measurement for therapeutic efficacy of interventions aiming at limiting infarct size since it normalizes the infarct size to MaR. Thus, the use of CMR and myocardial salvage index (rather than myocardial infarction size alone) substantially reduces the study group sizes needed to evaluate efficacy in clinical trials [
23]. It is therefore of utmost importance to develop feasible methods that accurately determine MaR in the clinical setting. Furthermore, the evaluation of the peri-infarct zone, which is also a feature of CMR evaluation, can add incremental prognostic value [
24].
Cardiovascular magnetic resonance evaluation of myocardium at risk
CMR is increasingly recognized as equivalent to nuclear-based techniques for determining the MaR whilst also having inherent practical advantages. Several CMR sequences have been evaluated in this context including CE-SSFP [
9,
11,
25,
26]. In 2012, Moral et al, compared BARI and APPROACH scores with T2-STIR and infarct endocardial surface area methods. They reported a good correlation between the different angiographic scores and their CMR-sequence [
27]. The data presented here, as far as we are aware, represent the first comparison of CE-SSFP and angiographic jeopardy scores in the literature.
The advantage of this method is that it can be easily added to current standard clinical protocols, in scanners from all major vendors, simply by administering a single dose of gadolinium contrast agent before acquiring short-axis cine images. This shortens the CMR protocol in the scanner and the evaluation time after the examination since the same images can be used both for MaR determination and the evaluation of functional parameters. Unstable patients may also benefit from shorter CMR protocols.
Bright-blood T2-weighted sequences have been developed to increase the diagnostic accuracy of T2 CMR for depicting edema [
28,
29]. One such sequence (ACUT2E) was more accurate for the determination of MaR and myocardial salvage than was dark-blood T2-weighted sequences, which results in underestimation of MaR [
30]. Thus, CE-SSFP might be more accurate than dark-blood T2 since CE-SSFP showed larger MaR in a study by Ubachs et al [
8]. Several limitations of different T2-weighted imaging protocols include a lack of consensus on the optimal quantification method, signal intensity variability within each slice and susceptibility to motion artefacts [
7,
31,
32]. Newly developed T1- or T2-mapping techniques may improve accuracy considerably on these limitations when using motion correction and an absolute threshold for edema, [
33‐
35] but further standardization and validation are still needed.
In patients, therefore, where there is no contraindication to gadolinium, the CE-SSFP may nevertheless still remain a more practical method to apply, particularly in time-constrained contemporary clinical working environments. Furthermore, the multi-phase acquisition of SSFP throughout the cardiac cycle allows for more robust delineation of endocardial and epicardial borders, less image artefacts, better spatial resolution, and as a consequence better inclusion rates of patients in clinical studies.
The mechanism for contrast-enhancement of the MaR during SSFP cannot be explained fully. The contrast in SSFP images is dependent on the sequence T2/T1 ratio. T2 relaxation times are based on the increase in tissue water content and mobility, which is a characteristic of MaR [
36]. When using a gadolinium-based contrast agent, the T1 for the surrounding tissue is shortened. This is also the rationale for infarct visualization in T1-weighted inversion-recovery LGE imaging since the contrast agent distributes to the extracellular space. Here the concentration of an extracellular gadolinium-based contrast agent is increased due to an increased distribution volume in myocardium injured by ischemia [
37‐
40]. It has been shown that even reversibly injured myocardium within the MaR has an increased distribution volume in the acute phase after an ischemic episode [
41,
42]. The T2/T1 ratio in the entire MaR, including both reversible and irreversibly injured myocardium, is affected by the presence of gadolinium. This might therefore explain the increased signal intensity in the MaR seen by CE-SSFP.
There is an ongoing scientific discourse regarding the conditioning treatments of reperfusion injury and their effect on myocardial edema. Two recent studies [
43,
44] have shown reduced MaR in the active group (local post-conditioning and remote pre-conditioning) of patients compared to controls, but the protocols and sequences used were not the same as the one used in our study. In addition, these studies used T2-STIR and T2-mapping respectively. The post-conditioning protocol in theory could have influenced the MaR calculated by CE-SSFP in the present study. The final infarct size and MaR, however, as judged by the extent of CE-SSFP and LGE was similar in both the control arm and post-conditioning arm. Furthermore, there were no differences in clinical outcomes between the groups. These observations suggest that any contribution of the treatment protocol to the MaR was minimal.
Collateral supply to an infarcted territory could also influence the final infarct size and MaR. Although there was no statistically significant difference between each of the angiographic quantification methods and the MaR for the extent of collateralization, there was a trend to significance with CE-SSFP evaluation (p = 0.157 and 0.06 respectively for Rentrop collaterals 0 vs a composite of Rentrop 2 and 3). This points to the intuitive consideration that CE-SSFP may have an added benefit as it takes the collateral supply into account whereas the rigid angiographic scoring techniques do not.
Angiographic evaluation of myocardium at risk
The modified–APPROACH score is based on pathological and necropsy studies and is derived from a template that considers the culprit artery, dominance and lesion location (proximal or mid-vessel) together with the size (small, medium or large) of the remaining major non-culprit epicardial vessel. The score in the template represents the percentage of left ventricle at risk.
The BARI score bases the anatomical area at risk and the length and caliber of the epicardial coronaries and has been validated against post-mortem histological studies [
21].
Both scores have been validated with respect to adverse clinical outcome in a large population-based cohort (20,067 patients) undergoing PCI with similar c-statistics for predicting one-year mortality, when added to simple baseline characteristics, of 0.85 and 0.84 for the APPROACH and BARI scores respectively [
22]. For both these angiographic scores their validity is based predominantly on left anterior descending and right coronary artery infarctions. Challenges in the electrocardiographic diagnosis of circumflex occlusion leads to under-representation of this category of infarction [
45].
The BARI score is more precise than the modified APPROACH score but is also more time-consuming. The modified APPROACH score on the other hand is subject to more observer variability. This study also reflects the broader variability of the latter compared to the former on Bland-Altman analysis. Whilst the BARI score takes into consideration stenotic lesions >50% and the Modified APPROACH score considers a lesion >70% as being significant, in the context of acute STEMI this difference in scoring is not manifest as the culprit vessel is occluded. The Modified APPROACH score is based on fixed assumptions of the myocardium at risk subtended by the location of a lesion in the coronary artery and hence clustering of high, intermediate and lower values can be seen when compared with CE-SSFP. There was no difference, however, in clinical outcomes and the absolute extent of infarction or in relation to MaR as estimated by either angiographic score or CE-SSFP. In addition, there was no difference in extent of infarction when adjusted for angiographically-evident collateralization. These data thus indicate that despite the precision of the BARI score, both angiographic techniques for estimating the size of MaR appeared to be clinically equivalent in this study.
Angiographic risk scores have been used to validate single-photon emission computed tomography as well as T2 weighted CMR [
7,
46].
This study was not able to disprove the hypothesis that there was no difference between angiographic scoring and CE-SSFP for the assessment of MaR, hence validating its use for this purpose. The close correlation between the angiographic and CE-SSFP measurements of myocardial area at risk adds further support that CE-SSFP may be a useful tool in studies investigating interventional, pharmacological and cardioprotective therapies in STEMI. These data and the practicality of adding early contrast enhancement to standard SSFP protocols, makes this a widely applicable method.
Limitations
The study was a single center retrospective analysis and thus subject to selection bias that may limit its external validity. The study was a post-hoc analysis from a parent study that was powered for clinical endpoints and so the analysis presented here is open to type 2 error. The results may have been influenced by the post-conditioning protocol and presence of collateral blood supply. The post-conditioning protocol, however, did not affect the overall infarct size. Furthermore, as infarct size was similar, an analysis on the differential predictive capacity for the techniques and infarct size based on therapy could not be performed
The angiographic jeopardy scores are based on anatomical assumptions and the relationships between these and other scoring systems in predicting clinical outcome is unclear.
No semi-quantitative method was used to determine MaR with the CE-SSFP sequence since the signal intensity difference between remote myocardium and MaR is small and makes it difficult to choose a fixed threshold value. Nevertheless, the inter-observer variability was excellent between the image readers. However, a new freely available semi-automatic software for estimating MaR using CE-SSFP has recently been validated and published [
19]. This program can be used in all major vendors and can further decrease variability as well as increase the accuracy in estimating MaR for future reperfusion studies.