Acute Microvascular Impairment Post-Reperfused STEMI Is Reversible and Has Additional Clinical Predictive Value

Objectives This study sought to investigate the clinical utility and the predictive relevance of absolute rest myocardial blood flow (MBF) by cardiac magnetic resonance (CMR) in acute myocardial infarction. Background Microvascular obstruction (MVO) remains one of the worst prognostic factors in patients with reperfused ST-segment elevation myocardial infarction (STEMI). Clinical trials have focused on cardioprotective strategies to maintain microvascular functionality, but there is a need for a noninvasive test to determine their efficacy. Methods A total of 64 STEMI patients post–primary percutaneous coronary intervention underwent 3-T CMR scans acutely and at 6 months (6M). The protocol included cine function, T2-weighted edema imaging, pre-contrast T1 mapping, rest first-pass perfusion, and late gadolinium enhancement imaging. Segmental MBF, corrected for rate pressure product (MBFcor), was quantified in remote, edematous, and infarcted myocardium. Results Acute MBFcor was significantly reduced in infarcted myocardium compared with remote MBF (MBFinfarct 0.76 ± 0.20 ml/min/g vs. MBFremote 1.02 ± 0.21 ml/min/g, p < 0.001), but it significantly increased at 6M (MBFinfarct 0.76 ± 0.20 ml/min/g acute vs. 0.85 ± 0.22 ml/min/g at 6M, p < 0.001). On a segmental basis, acute MBFcor had incremental prognostic value for infarct size at 6M (odds of no LGE at 6M increased by 1.4:1 [p < 0.001] for each 0.1 ml/min/g increase of acute MBFcor) and functional recovery (odds of wall thickening >45% at 6M increased by 1.38:1 [p < 0.001] for each 0.1 ml/min/g increase of acute MBFcor). In subjects with coronary flow reserve >2 or index of myocardial resistance <40, acute MBF was associated with long-term functional recovery and was an independent predictor of infarct size reduction. Conclusions Acute MBF by CMR could represent a novel quantitative imaging biomarker of microvascular reversibility, and it could be used to identify patients who may benefit from more intensive or novel therapies.

First-pass perfusion (FPP) by CMR for assessment of myocardial blood flow (MBF) (6) has been extensively used to estimate abnormal perfusion in patients with chronic artery disease (7), but a systematic investigation of MBF in acute STEMI is lacking.
By using MBF CMR, we sought to investigate: 1) the degree of microvascular impairment and its lon- Absolute Rest Myocardial Blood Flow After STEMI S E P T E M B E R 2 0 1 9 : 1 7 8 3 -9 3 recovery at 6M was assessed using a WT cutoff of 45% (9). Quantification of T 2 W edema and IS on LGE, both acutely and at 6M, was performed using a signal intensity threshold of 2 SD and 5 SD above the mean intensity of the remote reference region of interest (ROI), respectively, as previously described (10).   Values are mean AE SD, n (%), or median (first to third quartile).
CMR FINDINGS. The CMR findings are reported in Table 2. Acutely, all patients had positive edema, and only 1 had negative LGE; of 40 patients (63%) with MVO, 31 had also IMH. In 10 patients (i.e., 41 segments), myocardial edema persisted at 6M. Longitudinal native T1 changes relative to the degree of injury are also reported in Table 2 and Supplemental LGE, and LGE in combination with MVO were  A 100-ms change of T1 rather than a 1-s change, was used here to estimate the effect size because it is of the same order of magnitude as the T1 differences at the acute stage between remote myocardium and regions with ischemic injury.
These model predictions are in close agreement with the differences in acute MBF cor among tissue states that can be inferred from Table 2. At 6M, there was a significant, albeit small, overall improvement in MBF cor (0.04 ml/min/g, p < 0.001), independent of tissue state. 6M LGE with edema had a by 0.11 ml/ min/g worse effect than acutely (p ¼ 0.002).
Next, we investigated the association between MBF cor and native T1 as quantitative marker of severity of injury. Acutely, a 100-ms increase in myocardial T1 was associated with a significant MBF cor reduction of 0.10 AE 0.007 ml/min/g, whereas at 6M, an increase in native T1 by 100 ms was associated with a further MBF cor reduction by 0.05 AE 0.02 ml/min/g (p ¼ 0.001) ( Table 3, Figure 3). We found a negative association between MBF cor and T1 for all segments independent of the tissue state ( Figure 3).  Figure 2A).
Acute MBF cor had a significant effect on 6M LGE,  Borlotti et al.  Table 4, Figures 4A and 4B). As an example of point estimates from the model summarized in Table 4, we note that for segments with LGE of 50% and acute MBF cor of 0.3 ml/min/g, the predicted IS at 6M (34%) was w6% larger than in segments with the same LGE and an acute MBF cor of 0.8 ml/min/g (28% LGE at 6M) and w11% larger than in segments with same LGE and an acute MBF cor of 1.3 ml/min/g (23% LGE at 6M) ( Figure 4A). There was no evidence of an interaction between acute LGE and MBF cor for predicting 6M LGE.
In segments without LGE at 6M, 97% had no acute LGE, whereas the remaining 3% had a median acute LGE of 10.5%, which was resorbed over 6M.  show the predictions for wall thickening <45% as a function of acute myocardial blood flow corrected, and 0% and 50% late gadolinium enhancement, and with and without microvascular obstruction in the case of 50% acute late gadolinium enhancement. IS ¼ infarct size. and LGE, as shown in Figure 4B. The odds of no LGE at  Table 1.

DISCUSSION
The microcirculation plays a crucial role in infarct healing as the main supply conduit of oxygen and nutrients and as a delivery path for pharmacological treatments. An impairment in microvascular function is associated with a poor prognosis (12). To the best of our knowledge, this is the first CMR study using ab-  contrast, for areas with MVO, the underlying mechanisms promoting functional recovery and infarct reduction are less clear. The infarcted myocardium, once thought to be "dead," is actually a dynamic tissue undergoing an extensive process of remodeling, ultimately forming a core of scar, surrounded by neoangiogenesis in the infarct border zone (17,18) (4,22); however, we did not find a significant relationship between IMR and MVO/ MBF CULPRIT . There may be several reasons for this, including the small sample size and the assessment of resting perfusion rather than stress perfusion 3 days after the invasive coronary measurements (8).
Further larger studies are needed to corroborate our findings.