This is the first report to use CMR to characterize PIZ remodeling after myocardial infarction. There are two major findings in this study: 1) temporal changes in PIZ size can be detected with LGE-CMR, and 2) myocardial strain patterns change during the post-MI remodeling process.
Post-MI remodeling and the underlying substrate for PIZ-imaging
Cardiac wound repair, after MI, involves temporarily overlapping phases which include an inflammatory phase and tissue remodeling phase. The first phase starts shortly after coronary artery occlusion-- with or without reperfusion-- and involves degradation of normal extracellular matrix, invasion of inflammatory cells at the site of initial injury, and the induction of bioactive peptides and cytokines [
19]. Therefore, the early imaged MI substrate is characterized by a high cellularity, which is replaced by dense collagen fibers. These synthetic and degradative events, within the myocardial extra-cellular matrix, occur in a time and region-dependent manner following MI - which is reflected by histological and ultrastructural morphological changes. Within the MI region, the newly formed scar provides a means to tether viable myocyte fascicles, and thereby forms a substrate to resist deformation from the intra-cavitary stresses, generated during the cardiac cycle [
20,
21].
LGE-CMR imaging and PIZ assessment
Early CMR acquisitions for infarct size quantification in the acute phase are complicated by post-MI edema, which leads to an overestimation of the exact MI-size. Although the assessment of the PIZ may be influenced by the tissue edema, the PIZ (by CMR) still reflects the mixture of viable and infarcted myocardium.
Different techniques for analysis have been previously used to determine the PIZ in CMR. Specifically, the assessment of the PIZ is either defined with threshold techniques using standard deviations to the remote myocardium [
8], or based on modified FWHM criterion applying different signal intensities [
7,
22]. All of these methods claim to match the visual assessment of the PIZ by LGE-CMR. However, with the lack of quantitative histological reference, standard to index the heterogeneity of the PIZ, it is difficult to determine which method is superior over the other. In our analysis, we chose to use the 2 and 3 standard deviations threshold for this report and we found the best agreement with our visual assessment of the PIZ on LGE CMR images. In addition, we quantitatively assessed the PIZ with the FWHM criterion and found a similar remodeling pattern. We discovered that the quantified PIZ mass was larger with the FWHM method, compared to the threshold technique -- which confirms previous reports [
7,
8].
CMR has been used for risk stratification for ventricular arrhythmias following MI. Studies conducted in the 1980s show that a low LVEF predicts the risk of death after MI [
23,
24], and this data is currently used as one of the main criteria for ICD implantation [
25]. Subsequent studies demonstrate that infarct surface area and mass-- measured by CMR-- can more accurately identify patients at risk and present a substrate for monomorphic VT, when compared to LVEF [
26]. The ability to perform more detailed morphological analysis of the infarct scar will allow refined information on risk stratification [
7,
8].
Histologically, the early period of remodeling is characterized by the ongoing changes of the extracellular matrix and cell composition of tissue scar substrate, whereas the later period is characterized by a fixed substrate of cardiomyoctes and well-defined collagen scar [ref]. We demonstrate that the PIZ--assessed by LGE-CMR imaging-- undergoes significant changes early after MI as well. Until day 10, the PIZ decreases rapidly in mass and the PIZ mass stabilizes thereafter. Our data suggests that after 4 weeks post- MI, the PIZ can reliably evaluate structural remodeling. Additional information for regional strain analysis was acquired, which provides valuable information about the tensile forces working on the scar tissue and in the PIZ.
Recently, Fernandes
et al. showed that enhanced PIZ function, defined as greater Ecc and earlier time to peak Ecc, was associated with inducibility in patients with post MI heart failure [
27]. In our research, we did not see enhanced PIZ function at any particular time point during the remodeling process up to 90 days. However, at 30 days post-MI, we did observe a significant difference in Ecc and time to peak Ecc, between the infarct scar and PIZ, suggesting heightened mechanical stress working at the interface of viable and infarct tissue (Figure 6) [
28,
29]. Tensile forces working on the viable myocytes -- neighboring the scar tissue -- have been proposed for decades as crucial patho-physiological mechanisms, involved in post-MI remodeling and infarct expansion [
18]. Until now, this concept could not be experimentally verified using non-invasive imaging methods. A recent study demonstrated that circumferential strain rates are independent predictors of outcomes after MI and are predictive of cardiac remodeling following MI [
30]. However, Sasano
et al. reported the highest inducibility in a porcine model, 30 days after MI-induction [
31]. This is the same time-point that we observed the highest difference of strain between infracted area and PIZ in our pigs. The study of Sasano
et al. and our findings suggest that the underlying pathophysiology (of post-MI VT) can be elucidated with imaging techniques.
Limitations
The most significant limitation in this animal study was the inability to perform serial VT inducibilty studies with programmed stimulation. Having this data would help to determine the relationship between the imaged tissue substrate and susceptibility to VT. Another limitation was that all of the infarcts were created in the LAD territory, and were transmural. Strain patterns in the PIZ for non-transmural infarcts are expected to be very different from those in transmural infarcts, but our research did not explore this theory. Further, we did not acquire T2-weighted CMR images to quantify the post-MI edema, nor did we use any medications that are currently administered to patients in the post-MI period.