Pathophysiology of LV Remodeling Following STEMI

Background Adverse LV remodeling post–ST-segment elevation myocardial infarction (STEMI) is associated with a poor prognosis, but the underlying mechanisms are not fully understood. Diffusion tensor (DT)-cardiac magnetic resonance (CMR) allows in vivo characterization of myocardial architecture and provides unique mechanistic insight into pathophysiologic changes following myocardial infarction. Objectives This study evaluated the potential associations between DT-CMR performed soon after STEMI and long-term adverse left ventricular (LV) remodeling following STEMI. Methods A total of 100 patients with STEMI underwent CMR at 5 days and 12 months post-reperfusion. The protocol included DT-CMR for assessing fractional anisotropy (FA), secondary eigenvector angle (E2A) and helix angle (HA), cine imaging for assessing LV volumes, and late gadolinium enhancement for calculating infarct and microvascular obstruction size. Adverse remodeling was defined as a 20% increase in LV end-diastolic volume at 12 months. Results A total of 32 patients experienced adverse remodeling at 12 months. Compared with patients without adverse remodeling, they had lower FA (0.23 ± 0.03 vs 0.27 ± 0.04; P < 0.001), lower E2A (37 ± 6° vs 51 ± 7°; P < 0.001), and, on HA maps, a lower proportion of myocytes with right-handed orientation (RHM) (8% ± 5% vs 17% ± 9%; P < 0.001) in their acutely infarcted myocardium. On multivariable logistic regression analysis, infarct FA (odds ratio [OR]: <0.01; P = 0.014) and E2A (OR: 0.77; P = 0.001) were independent predictors of adverse LV remodeling after adjusting for left ventricular ejection fraction (LVEF) and infarct size. There were no significant changes in infarct FA, E2A, or RHM between the 2 scans. Conclusions Extensive cardiomyocyte disorganization (evidenced by low FA), acute loss of sheetlet angularity (evidenced by low E2A), and a greater loss of organization among cardiomyocytes with RHM, corresponding to the subendocardium, can be detected within 5 days post-STEMI. These changes persist post-injury, and low FA and E2A are independently associated with long-term adverse remodeling.


BACKGROUND
Following acute myocardial infarction (MI), reduced contractility in the left ventricle leads to an acute increase in loading conditions and triggers adaptive neurohormonal mechanisms. 1 Failure to normalize the increased wall stress results in progressive cavity dilatation and reduction in contractility, a process known as adverse remodeling, which is associated with reduced survival. 2 The exact mechanisms underpinning adverse remodeling are incompletely understood. Cardiac magnetic resonance (CMR) offers a range of techniques for quantifying edema, scarring, impairment in myocardial deformation, and contractility post-MI. The emergence of diffusion tensor (DT)-CMR now also permits the assessment of the organization and integrity of underlying microstructural components in vivo. 3 Reorientation of laminar "sheetlets" through the cardiac cycle correlates with myocardial strain and drives LV wall thickening in systole. In DT-CMR, the absolute secondary eigenvector angle (E2A) is a measure of the angularity of myocardial sheetlets. Global reduction in E2A during systole has been used to explain mechanistic deficiencies in wall strain and predict LV remodeling in patients with dilated cardiomyopathy. 3 In patients with MI, regional reduction in E2A in acutely infarcted segments has been shown to correlate with lower left ventricular ejection fraction (LVEF) at 3 months. 4 DT CMR can also characterize the helical arrangement of cardiomyocytes in vivo, as demonstrated on dissection plates. 5 In infarct segments, reductions in the proportion of myocytes with right-handed orientation (RHM) have been described, attributed to the loss of organization among subendocardial myocytes that is associated with lower LVEF post-MI. 4 DT-CMR can also infer tissue characteristics by measuring the mean diffusivity (MD) and fractional anisotropy (FA) of diffusion within the myocardium. MD can detect the presence of edema with higher signal contrast than T1 and T2 mapping, 6 as well as depicting areas of interstitial fibrosis. 7,8 Reduced FA can signify collagen infiltration and cardiomyocyte disorganization, 9,10 and it has been shown to be independently predictive of long-term LVEF post-MI. 4 Hence DT-CMR can provide mechanistic insights into the pathophysiologic mechanisms that drive adverse LV remodeling post-MI.
We therefore sought to: 1) explore baseline and long-term changes in DT-CMR parameters over 12 months post-ST-segment elevation myocardial infarction (STEMI); and 2) assess the potential association between early DT-CMR measures and longterm adverse remodeling.

METHODS
PATIENT RECRUITMENT. Patients with a first STEMI were prospectively recruited from a single tertiary center (The Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom) between 2019 and 2020.
Study inclusion criteria were: 1) acute STEMI as defined by current international guidelines; 11 2) revascularization by primary percutaneous coronary intervention (PCI) within 12 hours after onset of symptoms; and 3) no contraindications to CMR.
The study protocol was approved by The Institutional Acutely infarcted myocardium had higher mean diffusivity (MD) and lower fractional anisotropy (FA), suggesting that diffusion becomes more unrestricted and isotropic from edema and cardiomyocyte disorganization than remote myocardium. The myocardial sheetlets are unable to adopt their usual orientation in systole, as suggested by low absolute secondary eigenvector angle (E2A) values, and they have fewer myocytes with right-handed orientation (RHM) on helix angle maps, thus highlighting the early loss of organization among subendocardial myocytes. Acute infarct fractional anisotropy and secondary eigenvector angle were independently associated with adverse left ventricular (LV) remodeling at 12 months, with better accuracy than other cardiac magnetic resonance (CMR)-derived biomarkers.
DT ¼ diffusion tensor; STEMI ¼ ST-segment elevation myocardial infarction.     16 and the optimal thresholds were determined on the basis of the maximum Youden Index. All tests were assumed to be statistically significant when P < 0.05.

RESULTS
PATIENT CHARACTERISTICS. The Central Illustration outlines the main outcomes from this study. Figure 1 shows the study flowchart. Of the 150 enrolled patients, 100 (male-to-female ratio: 80:20, aged 59 AE 10 years) completed early (5 AE 2 days) and 12-month scans (391 AE 73 days); 43% of the patients presented with anterior STEMI ( Table 1).
DT-CMR ACQUISITION. The mean acquisition time for DT-CMR was 13 AE 5 minutes. Representative images are shown in Figure 2. In all patients, apical DT-CMR slices were not used for the final analysis because of frequent artifacts from unsuppressed fat, signal loss, and suboptimal signal-to-noise ratio.             For all variables, the variance inflation factor was <2. Tables 2 and 3.