Pathophysiology of LV Remodeling in Survivors of STEMI

Objectives The aim of this study was to investigate the clinical significance of native T1 values in remote myocardium in survivors of acute ST-segment elevation myocardial infarction (STEMI). Background The pathophysiology and prognostic significance of remote myocardium in the natural history of STEMI is uncertain. Cardiac magnetic resonance (CMR) reveals myocardial function and pathology. Native T1 (relaxation time in ms) is a fundamental magnetic resonance tissue property determined by water content and cellularity. Results A total of 300 STEMI patients (mean age 59 years; 74% male) gave informed consent. A total of 288 STEMI patients had evaluable native T1 CMR, and 267 patients (91%) had follow-up CMR at 6 months. Health outcome information was obtained for all of the participants (median follow-up 845 days). Infarct size was 18 ± 13% of left ventricular (LV) mass. Two days post-STEMI, native T1 was lower in remote myocardium than in the infarct zone (961 ± 25 ms vs. 1,097 ± 52 ms; p < 0.01). In multivariable regression, incomplete ST-segment resolution was associated with myocardial remote zone native T1 (regression coefficient 9.42; 95% confidence interval [CI]: 2.37 to 16.47; p = 0.009), as were the log of the admission C-reactive protein concentration (3.01; 95% CI: 0.016 to 5.85; p = 0.038) and the peak monocyte count (10.20; 95% CI: 0.74 to 19.67; p = 0.035). Remote T1 at baseline was associated with log N-terminal pro–B-type natriuretic peptide at 6 months (0.01; 95% CI: 0.00 to 0.02; p = 0.002; n = 151) and the change in LV end-diastolic volume from baseline to 6 months (0.13; 95% CI: 0.01 to 0.24; p = 0.035). Remote zone native T1 was independently associated with post-discharge major adverse cardiac events (n = 20 events; hazard ratio: 1.016; 95% CI: 1.000 to 1.032; p = 0.048) and all-cause death or heart failure hospitalization (n = 30 events during admission and post-discharge; hazard ratio: 1.014; 95% CI: 1.000 to 1.028; p = 0.049). Conclusions Reperfusion injury and inflammation early post-MI was associated with remote zone T1, which in turn was independently associated with LV remodeling and adverse cardiac events post-STEMI. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850)

Proof-of-concept studies in humans support the experimental observations (8,10). Local cytokine production from cardiomyocytes and macrophages represents an acute stress response to injury within the first week post-MI (9,11), leading to maladaptive matrix modifications that are associated with impaired contractility in the myocardial remote zone (7). Systemic inflammation is prognostically important post-MI (12), and evidence-based therapies for MI may reduce inflammatory activation (13).
Human tissue has fundamental magnetic properties, including the longitudinal (spin-lattice) proton relaxation time (native T1 in ms). Native T1 is influenced by water content, binding with macromolecules, and cell composition (14,15). Tissue water content increases as a result of ischemia, resulting in longer T1 times being a biomarker of more severe myocardial injury in localized myocardial regions (15)(16)(17). Cardiac magnetic resonance (CMR) now enables spatially resolved measurement of native T1 (T1 mapping) in the heart without using a gadolinium contrast agent that is normally required to delineate infarct tissue. However, the potential of native T1 to be used as a novel biomarker of heart injury in STEMI patients is not completely understood (7,(18)(19)(20)(21)(22)(23)(24) (Figure 1).
We hypothesized that regional myocardial tissue characteristics reflected by native T1 would be associated with the initial extent of ischemic injury and systemic inflammation. Our second hypothesis was that remote myocardial characteristics (native T1) would be independently associated with LV remodeling and pre-defined cardiovascular outcomes and mortality in the longer term.

METHODS STUDY POPULATION AND STEMI MANAGEMENT.
We performed a prospective CMR cohort study in a single November 22, 2012. A total of 343 STEMI patients provided written informed consent. The eligibility criteria included an indication for primary percutaneous coronary intervention (PCI) or thrombolysis for STEMI (25). Exclusion criteria represented standard contraindications to contrast CMR. Acute STEMI management followed contemporary guidelines (25,26). The study had ethics approval (reference 10-S0703-28) and was publically registered. Fifty healthy volunteers also underwent CMR (Online Appendix).
CMR ANALYSES. The CMR analyses are described in the Online Appendix.
T1-standardized measurements in myocardial regions of interest. LV contours were delineated with computerassisted planimetry on the raw T1 image and copied onto the color-encoded spatially coregistered maps.
Apical segments were not included because of partial volume effects. Particular care was taken to delineate regions of interest with adequate margins of separation from tissue interfaces prone to partial volume averaging, such as between myocardium and blood (27,28,33). The presence of off-resonance artifacts and cardiorespiratory motion was assessed by examination of the raw T1-weighted images. A total of 300 segments (8.6%) were excluded from analysis due to the presence of off-resonance or motion artifacts.
In STEMI patients, myocardial T1 values were segmented spatially and regions of interest were defined as: 1) remote myocardium; 2) injured myocardium; or 3) infarct core. The regions of interest were planimetered to include the entire area of interest with distinct margins of separation from tissue interfaces to exclude partial volume averaging. The remote myocardial region of interest was defined as myocardium 180 from the affected zone with no visible evidence of infarction, edema, or wall motion abnormalities (assessed by inspecting corresponding   contrast-enhanced T1-weighted, T2-weighted, or cine images, respectively). The infarct zone region of interest was defined as myocardium with pixel values (T1 or T2) >2 SD from remote myocardium on T2-weighted CMR (29)(30)(31). The infarct core was defined as an area in the center of the infarct territory having a mean T1 value of at least 2 SD below the T1 value of the periphery of the area at risk.
Infarct definition and size. The myocardial mass of late gadolinium (g) was quantified using computerassisted planimetry, and the territory of infarction was delineated using a signal intensity threshold of >5 SD above a remote reference region and expressed as a percentage of total LV mass (33).

PRE-SPECIFIED HEALTH
OUTCOMES. We prespecified adverse health outcomes that are pathophysiologically linked with STEMI. The primary  Table 1 and Online Table 2, respectively. Initial blood results on admission ¶ C-reactive protein, mg/l Values are mean AE SD, n (%), median (IQR), or range. The patients are grouped according to tertiles of remote zone native T1 (ms) at baseline. p values were obtained from 1-way analysis of variance, Kruskal-Wallis test, or Fisher test. *The p value is for the association between clinical characteristic and tertiles of remote zone native T1 at baseline. †Diabetes mellitus was defined as a history of diet-controlled or treated diabetes. ‡Successfully electrically cardioverted ventricular fibrillation at presentation or during emergency PCI procedure. §Killip classification of heart failure after acute myocardial infarction: class I ¼ no heart failure; class II ¼ pulmonary rales or crepitations, a third heart sound, and elevated jugular venous pressure; class III ¼ acute pulmonary edema; and class IV ¼ cardiogenic shock. kMultivessel coronary artery disease was defined according to the number of stenoses of at least 50% of the reference vessel diameter by visual assessment and whether or not there was left main stem involvement. ¶The blood results on admission and their changes during the first 2 days after admission are described in Online Remote zone native T1 was not associated with the number of coronary arteries affected by a stenosis of $50% severity or the culprit artery type.
The CMR findings are summarized in Table 2 (Figure 1). Forty-two T1 maps were unsuitable for analysis because of steady-state free precession off-resonance artifacts, and 19 of these T1 maps were also affected by motion artifacts. Remote zone native T1 values were higher than T1 values in infarct tissue (p < 0.001) and in infarct core (p < 0.001).
CMR findings at 6 months. The CMR findings at 6 months are described in Table 2.  Table 2).
The results of intraobserver and interobserver agreement of T1 measurements are shown in Online   Table 4).
Remote T1 was also multivariably associated with change in LV end-diastolic volume from baseline (n ¼ 267) (Online Figure 2, Online  The coefficient (95% CI) indicates the magnitude and direction of the difference in remote zone T1 (ms) for the patient characteristic (binary or continuous). For example, on average, remote zone native T1 (ms) 2 days post-MI was À9.93 (95% CI: À16.23 to À3.62) lower for male versus female, and native T1 (ms) was 0.14 (95% CI: 0.01 to 0.26) higher for each 1-ml increase in LV end-systolic volume. Previous MI affecting a territory of remote myocardium could alter native T1, which could be a confounding factor in the multivariable analysis of associates of remote zone native T1. In a sensitivity analysis involving backward stepwise variable selection, removing previous MI had no effect on the results of the multivariable models.
CI ¼ confidence interval; CRP ¼ C-reactive protein; other abbreviations as in Tables 1 and 2. The coefficient and 95% CI indicate the magnitude and direction of the difference in LV end-diastolic volume (ml) at follow-up for the patient characteristic (binary or continuous). For example, on average, LV end-diastolic volume (ml) at follow-up was 0.16 (95% CI: 0.05 to 0.27) higher for each 1-ms increase in remote zone native T1 measured by CMR at baseline. The univariable associations with LV end-diastolic volume at 6 months are described in the Online Appendix. *When area at risk was included instead of infarct size, remote zone T1 was also associated with LV end-diastolic volume at follow-up (0.25; 95% CI: 0.09 to 0.41; p ¼ 0.002).
Abbreviations as in Tables 1 to 3.
(NT-proBNP) results were available in 151 patients.
The clinical and CMR characteristics of these patients were similar to those of the whole cohort (Online Tables 6 and 7).  Table 8).
Remote zone native T1 was also associated with allcause death or heart failure hospitalization (n ¼ The net reclassification index and C-index indicated that adding remote zone native T1 did not alter the predictive value of the models (Online Appendix).

DISCUSSION
We used CMR to measure native T1 in myocardial regions of interest in a large cohort of STEMI survivors enrolled acutely during usual care, and we assessed the pathophysiology and prognostic importance of remote zone tissue.
The main findings of our study were: Our clinical findings are consistent with pre-clinical observations that monocytes participate in remote zone inflammation and remodeling (5-10) (Online Appendix). Remote zone native T1 was independently associated with LV remodeling at 6 months post-STEMI as revealed by CMR and NT-proBNP levels.
These observations explain why native T1 in remote myocardium early post-MI might influence longer-term prognosis because adverse remodeling is strongly associated with reduced survival post-MI (2). Acute inflammation early post-STEMI may be a target for therapy (5,13). Future studies should assess whether or not remote zone T1 might be influ-

CONCLUSIONS
In acute STEMI survivors, remote zone native T1 was temporally linked with reperfusion injury and inflammation and independently associated with LV remodeling and adverse cardiovascular outcomes.
The upper T1 tertile represents a potential cutoff for prognostication that merits further study.