Persistent Iron Within the Infarct Core After ST-Segment Elevation Myocardial Infarction

Objectives This study sought to determine the incidence and prognostic significance of persistent iron in patients post–ST-segment elevation myocardial infarction (STEMI). Background The clinical significance of persistent iron within the infarct core after STEMI complicated by acute myocardial hemorrhage is poorly understood. Methods Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction]). Cardiac magnetic resonance imaging including T2* (observed time constant for the decay of transverse magnetization seen with gradient-echo sequences) mapping was performed at 2 days and 6 months post-STEMI. Myocardial hemorrhage or iron was defined as a hypointense infarct core with T2* signal <20 ms. Results A total of 203 patients (age 57 ± 11 years, n = 158 [78%] male) had evaluable T2* maps at 2 days and 6 months post-STEMI; 74 (36%) patients had myocardial hemorrhage at baseline, and 44 (59%) of these patients had persistent iron at 6 months. Clinical associates of persistent iron included heart rate (p = 0.009), the absence of a history of hypertension (p = 0.017), and infarct size (p = 0.028). The presence of persistent iron was associated with worsening left ventricular (LV) end-diastolic volume (regression coefficient: 21.10; 95% confidence interval [CI]: 10.92 to 31.27; p < 0.001) and worsening LV ejection fraction (regression coefficient: −6.47; 95% CI: −9.22 to −3.72; p < 0.001). Persistent iron was associated with the subsequent occurrence of all-cause death or heart failure (hazard ratio: 3.91; 95% CI: 1.37 to 11.14; p = 0.011) and major adverse cardiac events (hazard ratio: 3.24; 95% CI: 1.09 to 9.64; p = 0.035) (median follow-up duration 1,457 days [range 233 to 1,734 days]). Conclusions Persistent iron at 6 months post-STEMI is associated with worse LV and longer-term health outcomes. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850)

M yocardial hemorrhage (1) and microvascular obstruction (2) are common and prognostically important complications of reperfused ST-segment elevation myocardial infarction (STEMI), and they are independently associated with adverse remodeling and heart failure in the longer term (2). The improvements in survival after acute STEMI in recent decades translate to more surviving patients with injured hearts who are at risk of developing longer-term complications (3,4). Because there are no evidence-based treatments for microvascular obstruction and myocardial hemorrhage, more research is needed to understand the pathophysiology of these disorders more fully.
Myocardial hemorrhage is a result of severe microvascular injury, with extravasation of erythrocytes secondary to loss of endothelial integrity (1,(5)(6)(7)(8). Hemoglobin degradation products are toxic (9)(10)(11), and their persistence is evidenced by immunohistochemical staining of iron within macrophages reflecting sustained inflammation within the infarct zone (10). Information relating to the clinical significance of persistent iron within the infarct core in patients with acute STEMI complicated by myocardial hemorrhage has been limited (e.g., sample size of n # 40 [11][12][13]), and prognostic data on health outcomes are lacking.
We aimed to determine the incidence of persistent iron in a large cohort of STEMI survivors using contemporary T 2 * (observed time constant for the decay of transverse magnetization seen with gradient-echo sequences) mapping (14,15). Additionally, we aimed to identify which clinical characteristics would be associated with persistent iron and whether persistent iron may be associated with adverse clinical outcomes.
We hypothesized that persisting iron would: 1) be associated with markers of the initial severity of STEMI; 2) present with distinct clinical characteristics when compared with resolved iron; 3) be associated with adverse myocardial remodeling; and 4) be associated with a worse prognosis in the longer term.

METHODS
The full methodology has been reported previously (16)(17)(18)(19) and is detailed in the Online Methods.  Regions of interest were drawn in the surrounding infarct and remote zones. The extent of myocardial edema was defined as LV myocardium with pixel values (T 2 ) >2 SD from remote myocardium (23,24).
Infarct definition and size. The territory of infarction was quantified using computer-assisted planimetry and was expressed as a percentage of LV mass (25).
Myocardial salvage. Myocardial salvage was calculated by subtraction of percentage of infarct size from percentage of myocardial edema (7,26,27). The myocardial salvage index was calculated by dividing the myocardial salvage area by the initial percentage of myocardial edema.
Adverse remodeling. Adverse remodeling was defined as an increase in LV end-diastolic volume at 6 months from baseline by 20% or more (17).
HEALTH OUTCOMES. We pre-specified adverse health outcomes that are implicated in the pathophysiology and natural history of STEMI. The primary composite outcome was all-cause death or first heart failure event (hospitalization for heart failure or defibrillator implantation) following the 6-month CMR scan. The secondary composite outcome was major adverse cardiac events (MACE).   Table 1  Compared with patients with resolved hemorrhage from baseline, patients with persistent iron were less likely to have a history of hypertension, and they had higher heart rates at presentation ( Table 1). The culprit artery was more likely to be the left anterior descending coronary artery, and these patients had higher peak troponin levels post-STEMI ( Table 1).
CMR FINDINGS. CMR findings were ascertained during the index hospitalization and at 6 months. The CMR findings are summarized in Table 2 and Online Table 2.  Table 2). There was no difference in T 2 signal in the infarct zone at baseline ( Table 2).
CMR findings at 6 months. In patients with persistent iron, the extent of hemorrhage or iron (percentage of infarct size) reduced in size from baseline to followup (26.2 AE 12.8% vs. 10.6 AE 9.4%; p < 0.001) ( Table 2).   Table 3 and Online Table 3. The main predictors of persisting iron in patients with acute hemorrhage were a higher heart rate at presentation, the absence of a history of hypertension, and infarct size ( Table 3).
PERSISTENT IRON AND LV REMODELING. In multivariable linear regression, persistent iron at 6 months was associated with worsening LV enddiastolic volume and worsening LV ejection fraction (Online Table 4, Online Figure 3).  1.09 to 9.64; p ¼ 0.035) ( Figure 2).

Associations with persistent iron and health
outcome were not independent of the initial size of the infarct.

DISCUSSION
We present a large investigation of persistent iron within the infarct core, as revealed by T 2 * mapping,  rare, whereas more recent studies indicated that persistent iron may be much more common (11,12,18 (5,11) have suggested that there is no association. Our results add to our idea that acute myocardial hemorrhage and persisting iron result from distinct pathological processes.