Circulating Small Extracellular Vesicles Reflect the Severity of Myocardial Damage in STEMI Patients

Abstract

Circulating small extracellular vesicles (sEVs) contribute to inflammation, coagulation and vascular injury, and have great potential as diagnostic markers of disease. The ability of sEVs to reflect myocardial damage assessed by Cardiac Magnetic Resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) is unknown. To fill this gap, plasma sEVs were isolated from 42 STEMI patients treated by primary percutaneous coronary intervention (pPCI) and evaluated by CMR between days 3 and 6. Nanoparticle tracking analysis showed that sEVs were greater in patients with anterior STEMI (p = 0.0001), with the culprit lesion located in LAD (p = 0.045), and in those who underwent late revascularization (p = 0.038). A smaller sEV size was observed in patients with a low myocardial salvage index (MSI, p = 0.014). Patients with microvascular obstruction (MVO) had smaller sEVs (p < 0.002) and lower expression of the platelet marker CD41-CD61 (p = 0.039). sEV size and CD41-CD61 expression were independent predictors of MVO/MSI (OR [95% CI]: 0.93 [0.87-0.98] and 0.04 [0-0.61], respectively). In conclusion, we provide evidence that the CD41-CD61 expression in sEVs reflects the CMR-assessed ischemic damage after STEMI. This finding paves the way for the development of a new strategy for the timely identification of high-risk patients and their treatment optimization.

Keywords: cardiac magnetic resonance; microvascular obstruction; myocardial infarction; platelets; small extracellular vesicles.

Figure 1

sEVs number (A–C) and size (D,E) were evaluated by NTA after isolation from plasma collected 3–5 days post STEMI. Patients were divided according to (A) STEMI site, (B) culprit lesion artery, (C) presentation time, (D) MSI (low <0.5; high >0.5), (E) MVO presence. Mean ± SD are reported. * p < 0.05; ** p < 0.01; *** p < 0.005. ant: anterior STEMI, non-ant: non-anterior STEMI, LAD: Left anterior descending artery, MVO: microvascular obstruction, MSI: myocardial salvage index.

Figure 2

Surface Epitope characterization of plasma sEVs. (A) Dot plot showing the MFI distribution for the reported antigens. (B) Network graph mapping the correspondence between the investigated antigens (circle node) and specific cell types (green hexagons); the color gradient and the node size represent the MFI expression from low (yellow and small nodes) to high (red and big nodes) level. Gray nodes denote not expressed antigens.

Figure 3

sEV expression of platelet marker CD41–CD61. Patients were divided according to (A) MVO presence, (B) STEMI site, (C) presentation time, (D) culprit lesion artery, (E) MSI (low <0.5; high >0.5). Mean ± SD are reported. * p < 0.05; ** p < 0.01.

Figure 4

CD41–CD61 expression and size discriminated patients with MVO/MSI. (A) ROC analysis was used to evaluate the ability of sEV profile (concentration, dimension, and CD41–CD61 expression) to identify patients with MVO and/or low MSI. Violet line: CD41–CD61 expression; brown line: dimension; green line: concentration; red line: troponin peak; blue line: Model including all the variables of sEV profile and troponin. (B) Patient with unfavorable CMR and sEV profile. A 69-year-old man with acute anterior STEMI: Three-chamber long axis view (i) and mid ventricle short axis view (ii) T2-weighted triple inversion recovery (TIR T2) images showing myocardial edema (yellow arrow) and myocardial hemorrhage (red arrow) at anteroseptal wall. (iii) Three-chamber long axis view cine image at end-systole, showing akinesia at mid-to-apical anteroseptal wall and apical inferolateral wall. (iv) Mid ventricle short axis view late gadolinium enhancement (LGE) image showing transmural enhancement (yellow arrow) and microvascular obstruction (light blue arrow) at anteroseptal wall. (C) Patient with favorable CMR and sEV profile. A 50-year-old man with acute inferolateral STEMI. (i) Basal ventricle short axis view TIR T2 image showing myocardial edema (yellow arrow) at inferolateral wall. (ii) Basal ventricle short axis view native T1 mapping image showing focal increased T1 values (up to 1372 msec; values at remote myocardium 1004 ± 30 msec) in line with focal myocardial damage (yellow arrow) at inferolateral wall. (iii) Basal ventricle short axis view cine image at end-systole, showing mild hypokinesia at inferolateral wall. (iv) Basal ventricle short axis view LGE image showing subendocardial enhancement involving 25–50% wall thickness (yellow arrow).