Relationship between CMR-derived parameters of ischemia/reperfusion injury and the timing of CMR after reperfused ST-segment elevation myocardial infarction

Cardioprotection after primary percutaneous coronary intervention (PPCI) involves therapy which reduced myocardial damage due to ischemia/reperfusion (I/R), with the aim of minimizing infarct size in patients with ST-segment elevation myocardial infarction (STEMI) [1]. This field is rapidly expanding and relies heavily on non-invasive imaging-based quantitative metrics of ischemic myocardial damage. In this sense, cardiovascular magnetic resonance (CMR) plays a crucial role given its ability to non-invasively depict and quantify the diverse components of ischemic damage with high precision and reproducibility [2]. Accordingly, several CMR-based parameters of I/R have been adopted as surrogate end-points in several cardioprotective studies, obviating costly and ethically questionable large clinical trials [2, 3]. Early after STEMI, CMR allows to measure IS, infarct-related myocardial edema, an estimate of area-at risk (AAR), as well as intramyocardial hemorrhage (IMH) and microvascular obstruction (MVO), two markers of microvasculature damage [2, 4]. However, recent studies have cast doubts about the reliability of these parameters when CMR is carried out early after reperfusion [5‐12]. In particular, they underpinned that infarct-related myocardial edema features a highly dynamic course after reperfusion rising concerns about the optimal timing of CMR. However, these studies were limited by small and selective study populations, and the time course of edema was rather heterogeneous as compared to pivotal experimental studies conducted in well-controlled I/R animal models [6‐9]. Indeed, in STEMI patients the pattern of infarct-related edema may be influenced by disparate poorly quantifiable factors, including the severity and duration of ischemia as well as spontaneous cardioprotection phenomena [9, 13]. Most important, the above studies relied largely on T2-weighted CMR for AAR quantification, which is less accurate, precise and robust than novel mapping techniques for edema quantification [14, 15].

Based on these premises, we studied a cohort of consecutive unselected reperfused STEMI patients using comprehensive CMR including mapping techniques during the index hospitalization to assess whether and to which extent the dynamics of edema influence CMR-derived parameters of I/R damage.

In a cohort of consecutive unselected STEMI patients treated by PPCI and undergoing comprehensive CMR during the index hospitalization, we found that T2-maps-based AAR quantification was independent of the timing of CMR after revascularization (T_Revasc-CMR). Although T2 values of the infarct region increased with increasing time interval between revascularization and CMR, T2 values of the infarct largely exceeded those of the remote myocardium yielding constant AAR despite the increase of T_Revasc-CMR. These findings were confirmed irrespective of presence or absence of IMH and of pre-PPCI residual flow in the myocardium at risk. Finally, LGE-dependent metrics, including infarct size and MVO occurrence and its extent, were independent of the timing of CMR after revascularization.

Recent reports generated intense discussion on the dynamic changes of CMR-derived measures of ischemic damage in early post-STEMI phase with particular emphasis on myocardial edema. In elegant experimental studies [6, 7, 9], Fernàndez-Jiménez et al. showed that edema features a bimodal pattern after reperfusion. An initial wave of edema appears abruptly and very early (≤3 h) to be attenuated at 24 h and followed by a second edema wave peaking at 4 to 7 days. The same group described this bimodal pattern in a selected cohort of 16 reperfused STEMI patients undergoing serial CMR (8). In patients, the authors found that T2 values within the ischemic region, as measured by T2-mapping, varied consistently throughout the post-reperfusion phase paralleling the experimental results. Accordingly, AAR, as quantified by T2-weighted short-TI (T2w-STIR), changed substantially with the timing of CMR being significantly lower at 24 h than at hyper-acute (≤3 h) or at 4 and 7 days after reperfusion. In line with these findings, we observed that T2 of the infarct increased with the increase of timing of CMR after revascularization, with a steep augmentation between Tertile-1 (median: 1.0 day) and Tertile-2 (median: 2.7 days) without further change between Tertile-2 and Tertile-3 (median: 5.3 days). However differently from the above study, we found that T2-map-derived AAR did not vary with the timing of CMR after PPCI. This discrepancy can be ascribed to the differences in study populations and, most importantly, to the different techniques utilized for AAR quantification. While Fernàndez-Jiménez’s et al. utilized T2w-STIR, we used T2-mapping, which allows more robust, precise and reproducible estimation of infarct-related edema as compared to T2w-STIR [14, 15]. Different from T2w-STIR imaging, T2-mapping consents to measure T2 lengthening of the ischemic tissue due to increased water content, rendering this techniques particular sensitive to subtle changes in T2 relaxation times [14, 17, 19]. Differently, T2-weightening relies on relative signal intensity differences between ischemic and remote myocardium, which are influenced by several factors in addition to edema per se, such as specific T2-weightening parameters, motion-related signal loss in the lateral wall or selection of window/leveling to display images [15]. Accordingly, slight differences in T2 relaxation times between ischemic and remote myocardium, such as those reported in the experimental and clinical studies by Fernàndez-Jiménez et al. [6‐9] at 24-h after reperfusion, might have been overlooked by T2w-STIR leading to underestimation of AAR. In our study, T2 values of infarct myocardium exceeded largely those of remote region irrespective of the time interval between revascularization and CMR, the presence or absence of IMH, and pre-PPCI residual blood flow in the myocardium at risk. Accordingly, we were able to quantify AAR on T2-maps using a semi-automatic threshold-based algorithm in the overall population and specific subgroups [17]. Moreover, the pattern of T1 values in infarct and remote myocardium paralleled closely that of T2, corroborating our study results. Experimentally T1 relaxation time increases in parallel with increasing myocardial water content, and prolonged T1 has been reported in myocardium at risk in STEMI patients [20, 21].

In summary, our data confirm the dynamic course of T2 in ischemic and remote myocardium as reported by others [6‐9]. However, these changes do not translate into systematic variation of T2-mapping-based AAR quantification, given the high sensitivity of this technique in capturing subtle difference in T2 relaxation time between ischemic and remote myocardium [14, 17].

In Tertile-1, we found that patients with residual blood flow within AAR had lower infarct T2 values as compared to those without. Leftover blood flow in the territory at risk via either the infarct-related artery or collaterals is effective in protecting the myocardium from ongoing necrosis [22, 23]. Accordingly, recent evidences suggested that the severity of edema, as quantified by the lengthening of infarct T2 values, may be influenced by infarct-limiting interventions [9, 24]. Thus, cardioprotective strategies may reduce infarct T2 values, and further dedicated studies are need to specifically tackle this controversial aspect.

We also found that IMH influenced the pattern of T2 within infarct so that patients with IMH had a constant augmentation of T2 relaxation time after reperfusion. Moreover, Tertile-1 patients with IMH tended to have higher infarct T2 values than patients without IMH (P = 0.082). This result is in line with experimental data reporting that after reperfusion the increase of T2 values and water content in the infarct region were associated with the severity of IMH [6‐9]. Overall the evidence converges in supporting the concept that IMH is not necessarily associated with a decrease of infarct T2 values, likely because T2 relaxation time represents the equipoise between the destructive paramagnetic effects of deoxyhemoglobin (T2 decline) and the increase of tissue water content (T2 raise), [6‐9].

Finally, we observed that LGE-based estimate of infarct size was independent of the timing of CMR after reperfusion. This finding diverges from some previous clinical studies, which reported a time dependency of LGE extent prompting an overestimation of infarct size when CMR was performed early after reperfusion [9‐12]. However, most of these studies included a small number of patients, and the first CMR was performed at 24 h and then repeated 1 week or later not allowing to adequately tracking infarct healing. In contradistinction, we divided the study cohort according to the timing of CMR after reperfusion. The tertiles thus obtained included more than 50 subjects for each, and they were evenly balanced with respect to clinical factors influencing I/R damage [13]. This allowed superseding some of the previous study limitations and to investigate how LGE-derived infarct size was influenced by the timing of CMR throughout a broad interval spanning from 6 h to 14 days after reperfusion. Furthermore, we measured ECV of the infarct region in patients without MVO, and this parameter remained stable across T_revasc-CMR tertiles, providing a mechanistic insight about the independency of LGE-derived infarct size from the timing of CMR.

This study has several limitations. Firstly, it was conducted in a tertiary referral center for PPCI and CMR. Accordingly, we cannot exclude a referral bias. T_revasc-CMR tertiles showed an even distribution of clinical and hemodynamic factors influencing I/R damage [11]. However, our study design cannot completely remove bias in allocating subjects to the 3 tertiles. Ideally, this limitation can be overcome by repeating CMR at fixed time points in large cohort of patients. However, this type of study entails complex protocols arising also ethical concerns due to repeated administration of gadolinium-based contrast agent for IS. To the best of our knowledge the largest study serially repeating contrast-enhanced CMR in the early post-STEMI included only 30 patients [5]. We did not use T2*-mapping for IMH identification and quantification to obviate to off-resonance artifacts which are particularly cumbersome at interface between myocardium and lung [25].

In this study including consecutive unselected reperfused STEMI patients, CMR-derived parameters of I/R damage were not influenced by the timing of CMR after reperfusion. Although we acknowledge dynamic changes of T2 relaxation time of the infarct and the remote myocardium after revascularization, however these variations did not influence T2-mapping-derived AAR or LGE-based infarct size. Accordingly, CMR remains a valid non-invasive imaging modality for characterizing and quantifying the diverse components of I/R damage in STEMI patients during the early post-infarction phase.