The study at hand has compared absolute measures of
18F-FDG uptake, extracellular volume and native T
1 in patients early after revascularized myocardial infarction using simultaneously acquired PET/CMR data. Quantitative results have been derived for a single, infarct-centric slice position that was co-localized between all three methods, which can be seen as a biopsy-like imaging approach. An effort was made to link the so-obtained image signals to underlying pathophysiological processes using independent measures of infarct size and peripheral blood markers of cardiac damage and inflammatory cell populations. The study did not investigate correlations between image signals and functional recovery post AMI as these have already been given separately for ECV [
11],
18F-FDG [
15] and native T
1 [
9] in quantitative or semi-quantitative fashion.
Comparison of signal localization and magnitude
The first step was the comparison of inter-patient and intra-patient (i.e. intra-slice) signals as shown in Fig.
2. The excellent correlations for the latter suggest a very good co-localization of pathophysiological processes indicated by the three different image signals. While in the vast majority of studies, extents of image signals are compared by global thresholding, e.g. using multiples of standard deviations as binary cutoff values, the intra-patient correlations shown herein are independent of differences in absolute signal increase between patients, i.e. differences seen in the correlation slopes in Fig.
2c-d. Despite the good co-localization of signal increases, the heterogeneity of these slopes and equivalently the comparison of maximum values in Fig.
3 suggest sensitivities to different underlying tissue properties. Therefore, ECV,
18F-FDG uptake and native T
1 appeared as representing mutually distinct combinations of features with respect to infarct-related pathophysiology, while the respective underlying processes seemed to be largely co-localized.
Comparison of signal magnitudes and external markers
For myocardial ECV, estimates derived from pre- and post-contrast T
1 mapping have been shown to be sensitive to a number of different disease processes [
5] and histologically verified to correlate with fibrosis [
24]. With respect to AMI, quantitative ECV mapping has only recently been shown to be associated with functional outcome in patients [
11] but further investigation of pathophysiological mechanisms are lacking. While significant association of ECV with edema has been documented at day 1 after AMI in pigs [
25], the same study reported a disappearance of this association after 7 days, which suggests edema if at all as a minor contributor to ECV estimates from the study at hand obtained 5 days after AMI. A possible pathophysiological correlate for absolute ECV in this study has been provided in the form of CK/CK-MB blood markers for (myocytic) cellular damage. The significant correlation between peak CK-MB and ECV is in fact remarkable as it reflects the association of a global, peripheral blood parameter with a focal, biopsy-like imaging result. It may however be seen as an epiphenomenon to the additional finding of a highly significant correlation between ECV at the infarct center and infarct size, where peak CK-MB activity is an established marker for the latter [
26]. This observed relationship between the extent of the area being subject to ischemic insult and the amount of myocytic damage at its center may be seen as somewhat mechanistically plausible, considering a decrease of the probability for remaining collateralization with distance to the nearest non-infarcted tissue regions. The much smaller significance for the corresponding correlation observed between peak CK and ECV is consistent with a lower specificity of CK to myocardial damage compared to CK-MB.
With respect to FDG, data from this study suggest no correlation of maximum
18F-FDG uptake at the infarct center with peak monocyte or leukocyte counts or global infarct size. This was irrespective of whether maximum
18F-FDG was evaluated in absolute terms as SUV LBM or normalized to LV blood activity as a TBR. A similar finding [
15] has been interpreted as a conceivable disproportionality between systemic/peripheral inflammatory cell counts and the presence of migrated inflammatory cells within the myocardium begetting the imaging signal. While it is known that
18F-FDG is taken up by inflammatory cell populations [
27], the interpretation of a corresponding image signal from the post-ischemic myocardium is challenging due to the concurrent presence of background contributions from myocyte uptake. Despite a somewhat reliable suppression of physiologic FDG metabolism in healthy cardiomyocytes, the potential presence of post-ischemic FDG uptake due to a switch of metabolism from fatty acids towards glucose consumption early after AMI is a major confounder to the interpretation of
18F-FDG uptake as a purely inflammatory signal [
28]. Therefore,
18F-FDG image signals are generally regarded as a mixture of background/blood pool, post-ischemic and inflammatory constituents in this context.
Native myocardial T
1 may reflect a variety of pathologic tissue alterations, but is generally accepted to indicate the edematous increase of free water content early after AMI [
8]. The expected increase of infarct-centric native T
1 observed in this study is therefore attributed to an edematous reaction, which, however, did not show a correlation with infarct size as ECV did. With respect to native T
1, the most interesting finding from this study is a highly significant correlation with peak monocyte counts and a weaker but still significant association to peak leukocyte counts, of which monocytes are a subset specific to inflammatory activity. As for ECV, this association of biopsy-like imaging results with peripheral blood markers is remarkable, even more so considering that native T
1 was not found to be related to infarct size. Therefore, the data at hand provides evidence for the fact that myocardial edema and the systemic inflammatory reaction post AMI are quantitatively associated.
Summarizing the comparison of imaging results with peripheral blood parameters, the data at hand suggest ECV as a marker of cellular damage early after reperfused AMI, with maximum values related to infarct size and therefore reflecting most likely a mechanistic property of the respective infarct. Conversely, the missing correlation to infarct size for maximum 18F-FDG uptake and native T1 suggest their association with a more patient- than infarct-specific reaction to the ischemic insult. This notion is strongly supported by the observed association of native T1 with peak monocyte counts.
Limitations
An important translational limitation to results from this study is that patients exhibiting MVO post AMI were not amenable to the presented analysis. While there exist propositions on the segmentation of MVO border zones for e.g. ECV mapping [
11], the difference in spatial resolution between PET and CMR precluded comparable sub-segmentations of the myocardial wall. For similar reasons, only transmural short-axis sectors were defined for LV myocardium, where especially cardiac motion hampers a meaningful sub-segmentation across the myocardial wall in PET. With respect to segmentation, locations for maximum values were determined individually for each modality because the alternative of having one of the three methods be the reference standard for locating the corresponding sectors would have introduced a bias into the comparison and additionally precluded the translation of conclusions to situations where the reference modality is not available. The small spatial differences introduced by individual determination of reference sectors did not suggest this as a significant limitation to the finding that all three modalities indicate mutually distinct processes within the tissue.
The acquisition scheme (3(3)3(3)6) used in this study for MOLLI T
1 mapping has been shown to be more sensitive to variations in heart rate than other, more recently proposed schemes [
29]. However, the fact that resting heart rates in the examined cohort did not vary strongly and that heart rate did not correlate with remote native T
1 (
R = − 0.22,
p = 0.3) do not suggest this as a major confounder to the presented findings.
Additionally, the practice of using peak values of peripheral blood markers as a surrogate for their summed activity may have introduced additional variability into the reported results. While the described practice is known to be relatively accurate for CK/CK-MB [
26], the inflammatory reaction indicated by monocyte counts may behave in a more complex fashion. With respect to statistics, the large number of performed correlation analyses may have justified the use of a 1% significance level to make type 1 errors less likely. However, the main conclusions presented herein only rely on findings with
p-values < 0.01.