The Year in Cardiology 2018: Acute Coronary Syndromes

Petr Widimsky; Filippo Crea; Ronald K. Binder; Thomas F. Lüscher


Eur Heart J. 2019;40(3):271-282. 

In This Article


Alterations of Innate and Adaptive Immunity

In patients with ACS, the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1–5 leads to uncontrolled lymphocyte activation. Flego et al.[18] found that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1–5 in CD4+ T-cells of ACS patients. They propose the following sequence of events in ACS and systemic evidence of inflammation: MMP-9, released by innate immunity cells and by T-cells, causes the cleavage of CD31 domain 1–5; the increased expression of MMP-9 might affect TCR-dependent T-cell activation and induce T-cell hyper-reactivity, through the alteration of cellular pathways linked to CD31 cleavage. They also propose that molecules such as MMP-9 and CD31, could represent desirable molecular targets for specific anti-inflammatory treatments and might be used as clinical biomarkers of prognosis in patients with ACS.

Plaque Erosion on the Rise

At least one-third of ACS are caused by plaque erosion and with its recognition the prevalence is probably increasing.[19] Dai et al. assessed the culprit plaque in 822 patients present STEMI by optical coherence tomography (OCT) and found that plaque erosion was a predictable clinical entity distinct from plaque rupture in STEMI patients. Indeed, at the multivariable analysis, age <50 years, current smoking, absence of other coronary risk factors, lack of multi-vessel disease, reduced lesion severity, larger vessel size, and nearby bifurcation were significantly associated with plaque erosion.[20] Substantial differences between plaque erosion and plaque fissure were also found by Sugiyama et al.[21] who performed three-vessel OCT in 51 patients with ACS and observed that compared with those with culprit plaque rupture, patients with plaque erosion had a smaller number of nonculprit plaques and the lower levels of panvascular instability, affirming that distinct pathophysiologic mechanisms operate in plaque erosion and plaque rupture.

Finally, in a mechanistic study, Pedicino et al.[22] evaluated the gene/protein expression of HYAL2 (enzyme degrading hyaluronan to its pro-inflammatory 20 kDa isoform) and of the hyaluronan-receptor CD44 (Figure 2). Gene and protein expression of HYAL2 and CD44v6 were higher in patients with plaque erosion when compared with those with plaque rupture. HYAL2 might represent a potential new biomarker in ACS. This clinical study shows that plaque erosion is characterized by a profound alteration of hyaluronan metabolism and that, after further validation, HYAL2 might represent a potentially useful biomarker for the non-invasive identification of this mechanism of coronary instability.

Figure 2.

Model of plaque erosion. The figure summarizes the driving hypothesis that derives from both the existing experimental and post-mortem studies on plaque erosion and the data emerging from this clinical study. Overexpression of hyaluronidase 2 in peripheral blood mononuclear cells (membrane, cytoplasm, and nuclei) under conditions of increased shear stress (#1) leads to degradation of high-molecular-weight hyaluronan to proinflammatory low-molecular-weight hyaluronan, which, in turn, promotes endothelial activation and detachment via TLR2 stimulation (#2), as well as neutrophil recruitment (#3), the latter being amplified by overexpression of CD44, which is necessary and sufficient for adhesion of neutrophils to low-molecular-weight hyaluronan. Finally, low-molecular-weight hyaluronan induces increased platelet-monocyte binding, thus promoting thrombus formation (#4). Scarcely represented inflammatory cells are found in the intima, close to the site of erosion (T-cells in green and foam cells). EC, endothelial cell; ECM, extracellular matrix; HA, hyaluronan; HMW-HA, high-molecular-weight hyaluronan; HYAL2, hyaluronidase 2; LMW-HA, low-molecular-weight hyaluronan; PBMC, peripheral blood mononuclear cell; PMNc, polimorphonuclear cell (from Sugiyama et al.21).

New Insight Into Post-myocardial Infarction Remodelling

In an elegant experimental study Reboll et al.[23] identified Emc10 as a previously unknown angiogenic growth factor that is produced by bone marrow-derived monocytes and macrophages as part of an endogenous adaptive response that can be enhanced therapeutically to repair the heart after MI. In another study, Miyazaki et al. investigated whether osteocrin (OSTN) potentially functioning as a natriuretic peptide clearance receptor-blocking agent can be used as a new therapeutic peptide for treating congestive heart failure after MI. In a mouse model they found that infusion of OSTN[24] resulted in an increased plasma atrial natriuretic peptide and in an improvement of congestive heart failure after MI as indicated by the reduced weight of hearts and lungs and by the reduced fibrosis. Similar results were confirmed in a transgenic model overexpressing OSTN. Finally, Frankenreiter et al. in a preclinical study found that lack of BK mitochondrial channels renders the heart more susceptible to ischaemia/reperfusion injury, while BK channels seem to permit the protective effects triggered by PDE5 inhibitors as well as by preconditioning. Thus, this study establishes mitochondrial cardiomyocyte BK channels as a promising target for limiting acute cardiac damage as well as adverse long-term events that occur after MI.[25]